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BigScience Biomedical Datasets 114

[ { "id": "10841811__text", "type": "abstract", "text": [ "Segregation analysis of esophageal cancer in a moderately high-incidence area of northern China. In order to explore the mode of inheritance of esophageal cancer in a moderately high-incidence area of northern China, we conducted a pedigree survey on 225 patients affected by esophageal cancer in Yangquan, Shanxi Province. Segregation analysis was performed using the REGTL program of S.A.G.E. The results showed that Mendelian autosomal recessive inheritance of a major gene that influences susceptibility to esophageal cancer provided the best fit to the data. In the best-fitting recessive model, the frequency of the disease allele was.2039. There was a significant sex effect on susceptibility to the disease. The maximum cumulative probability of esophageal cancer among males with the AA genotype was 100%, but, among females, it was 63.5%. The mean age at onset for both men and women was 62 years. The age-dependent penetrances for males with the AA genotype by the ages of 60 and 80 years were 41.6% and 95.2%, respectively, whereas, for females, they were 26.4% and 60.5%, respectively. Incorporating environmental risk factors-such as cigarette smoking, pipe smoking, alcohol drinking, eating hot food, and eating pickled vegetables-into the models did not provide significant improvement of the fit of the models to these data. The results suggest a major locus underlying susceptibility to esophageal cancer with sex-specific penetrance.\n" ], "offsets": [ [ 0, 1453 ] ] } ]

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[ { "id": "10775524__text", "type": "abstract", "text": [ "Identification of uniparental disomy following prenatal detection of Robertsonian translocations and isochromosomes. Rearrangements of the acrocentric chromosomes (Robertsonian translocations and isochromosomes) are associated with an increased risk of aneuploidy. Given this, and the large number of reported cases of uniparental disomy (UPD) associated with an acrocentric rearrangement, carriers are presumed to be at risk for UPD. However, an accurate risk estimate for UPD associated with these rearrangements is lacking. A total of 174 prenatally identified acrocentric rearrangements, including both Robertsonian translocations and isochromosomes, were studied prospectively to identify UPD for the chromosomes involved in the rearrangements. The overall goal of the study was to provide an estimate of the risk of UPD associated with nonhomologous Robertsonian translocations and homologous acrocentric rearrangements. Of the 168 nonhomologous Robertsonian translocations studied, one showed UPD for chromosome 13, providing a risk estimate of 0.6%. Four of the six homologous acrocentric rearrangements showed UPD, providing a risk estimate of 66%. These cases have also allowed delineation of the mechanisms involved in producing UPD unique to Robertsonian translocations. Given the relatively high risk for UPD in prenatally identified Robertsonian translocations and isochromosomes, UPD testing should be considered, especially for cases involving the acrocentric chromosomes 14 and 15, in which UPD is associated with adverse clinical outcomes.\n" ], "offsets": [ [ 0, 1558 ] ] } ]

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[ { "id": "10712193__text", "type": "abstract", "text": [ "James V. Neel, M.D., Ph.D. (March 22, 1915-January 31, 2000): founder effect.\n" ], "offsets": [ [ 0, 78 ] ] } ]

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[ { "id": "10712209__text", "type": "abstract", "text": [ "Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. A previous linkage study provided evidence for a prostate cancer-susceptibility locus at 1q24-25. Subsequent reports in additional collections of families have yielded conflicting results. In addition, evidence for locus heterogeneity has been provided by the identification of other putative hereditary prostate cancer loci on Xq27-28, 1q42-43, and 1p36. The present study describes a combined analysis for six markers in the 1q24-25 region in 772 families affected by hereditary prostate cancer and ascertained by the members of the International Consortium for Prostate Cancer Genetics (ICPCG) from North America, Australia, Finland, Norway, Sweden, and the United Kingdom. Overall, there was some evidence for linkage, with a peak parametric multipoint LOD score assuming heterogeneity (HLOD) of 1.40 (P=.01) at D1S212. The estimated proportion of families (alpha) linked to the locus was.06 (1-LOD support interval.01-.12). This evidence was not observed by a nonparametric approach, presumably because of the extensive heterogeneity. Further parametric analysis revealed a significant effect of the presence of male-to-male disease transmission within the families. In the subset of 491 such families, the peak HLOD was 2.56 (P=.0006) and alpha =.11 (1-LOD support interval.04-.19), compared with HLODs of 0 in the remaining 281 families. Within the families with male-to-male disease transmission, alpha increased with the early mean age at diagnosis (<65 years, alpha =.19, with 1-LOD support interval.06-.34) and the number of affected family members (five or more family members, alpha =.15, with 1-LOD support interval.04-.28). The highest value of alpha was observed for the 48 families that met all three criteria (peak HLOD = 2.25, P=.001, alpha=.29, with 1-LOD support interval.08-.53). These results support the finding of a prostate cancer-susceptibility gene linked to 1q24-25, albeit in a defined subset of prostate cancer families. Although HPC1 accounts for only a small proportion of all families affected by hereditary prostate cancer, it appears to play a more prominent role in the subset of families with several members affected at an early age and with male-to-male disease transmission.\n" ], "offsets": [ [ 0, 2401 ] ] } ]

[ { "id": "10712209_T1", "type": "Gene", "text": [ "HPC1" ], "offsets": [ [ 2146, 2150 ] ], "normalized": [] } ]

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[ { "id": "10739770__text", "type": "abstract", "text": [ "The gene for May-Hegglin anomaly localizes to a <1-Mb region on chromosome 22q12.3-13.1. The May-Hegglin anomaly (MHA) is an autosomal dominant platelet disorder of unknown etiology. It is characterized by thrombocytopenia, giant platelets, and leukocyte inclusion bodies, and affected heterozygotes are predisposed to bleeding episodes. The MHA gene has recently been localized, by means of linkage analysis, to a 13.6-cM region on chromosome 22, and the complete chromosome 22 sequence has been reported. We recently performed a genome scan for the MHA gene in 29 members of a large, multigenerational Italian family, and we now confirm that the MHA locus is on chromosome 22q12. 3-13.1. The maximal two-point LOD score of 4.50 was achieved with the use of marker D22S283, at a recombination fraction of.05. Haplotype analysis narrowed the MHA critical region to 6.6 cM between markers D22S683 and D22S1177. It is of note that the chromosome 22 sequence allowed all markers to be ordered correctly, identified all the candidate genes and predicted genes, and specifically determined the physical size of the MHA region to be 0. 7 Mb. These results significantly narrow the region in which the MHA gene is located, and they represent the first use of chromosome 22 data to positionally clone a disease gene.\n" ], "offsets": [ [ 0, 1309 ] ] } ]

[ { "id": "10739770_T1", "type": "Gene", "text": [ "MHA" ], "offsets": [ [ 342, 345 ] ], "normalized": [] }, { "id": "10739770_T2", "type": "Gene", "text": [ "MHA" ], "offsets": [ [ 551, 554 ] ], "normalized": [] }, { "id": "10739770_T3", "type": "Gene", "text": [ "MHA" ], "offsets": [ [ 648, 651 ] ], "normalized": [] }, { "id": "10739770_T4", "type": "Gene", "text": [ "MHA" ], "offsets": [ [ 842, 845 ] ], "normalized": [] }, { "id": "10739770_T5", "type": "Gene", "text": [ "MHA" ], "offsets": [ [ 1110, 1113 ] ], "normalized": [] }, { "id": "10739770_T6", "type": "Gene", "text": [ "MHA" ], "offsets": [ [ 1195, 1198 ] ], "normalized": [] } ]

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[ { "id": "10915611__text", "type": "abstract", "text": [ "Rare etiology of autosomal recessive disease in a child with noncarrier parents. A child with maple syrup urine disease type 2 (MSUD2) was found to be homozygous for a 10-bp MSUD2-gene deletion on chromosome 1. Both purported parents were tested, and neither carries the gene deletion. Polymorphic simple-sequence repeat analyses at 15 loci on chromosome 1 and at 16 loci on other chromosomes confirmed parentage and revealed that a de novo mutation prior to maternal meiosis I, followed by nondisjunction in maternal meiosis II, resulted in an oocyte with two copies of the de novo mutant allele. Fertilization by a sperm that did not carry a paternal chromosome 1 or subsequent mitotic loss of the paternal chromosome 1 resulted in the propositus inheriting two mutant MSUD2 alleles on two maternal number 1 chromosomes.\n" ], "offsets": [ [ 0, 823 ] ] } ]

[ { "id": "10915611_T1", "type": "Gene", "text": [ "MSUD2" ], "offsets": [ [ 174, 179 ] ], "normalized": [] }, { "id": "10915611_T2", "type": "Gene", "text": [ "MSUD2" ], "offsets": [ [ 771, 776 ] ], "normalized": [] } ]

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[ { "id": "10712225__text", "type": "abstract", "text": [ "A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters. Large intergenerational repeat expansions of the CAG trinucleotide repeat in the HD gene have been well documented for the male germline. We describe a recurrent large expansion of a maternal allele with 36 CAG repeats (to 66 and 57 repeats, respectively, in two daughters) associated with onset of Huntington disease (HD) in the second and third decade in a family without history of HD. Our findings give evidence of a gonadal mosaicism in the unaffected mother. We hypothesize that large expansions also occur in the female germline and that a negative selection of oocytes with long repeats might explain the different instability behavior of the male and the female germlines.\n" ], "offsets": [ [ 0, 787 ] ] } ]

[ { "id": "10712225_T1", "type": "Gene", "text": [ "HD" ], "offsets": [ [ 186, 188 ] ], "normalized": [] } ]

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[ { "id": "10712212__text", "type": "abstract", "text": [ "The distribution of human genetic diversity: a comparison of mitochondrial, autosomal, and Y-chromosome data. We report a comparison of worldwide genetic variation among 255 individuals by using autosomal, mitochondrial, and Y-chromosome polymorphisms. Variation is assessed by use of 30 autosomal restriction-site polymorphisms (RSPs), 60 autosomal short-tandem-repeat polymorphisms (STRPs), 13 Alu-insertion polymorphisms and one LINE-1 element, 611 bp of mitochondrial control-region sequence, and 10 Y-chromosome polymorphisms. Analysis of these data reveals substantial congruity among this diverse array of genetic systems. With the exception of the autosomal RSPs, in which an ascertainment bias exists, all systems show greater gene diversity in Africans than in either Europeans or Asians. Africans also have the largest total number of alleles, as well as the largest number of unique alleles, for most systems. GST values are 11%-18% for the autosomal systems and are two to three times higher for the mtDNA sequence and Y-chromosome RSPs. This difference is expected because of the lower effective population size of mtDNA and Y chromosomes. A lower value is seen for Y-chromosome STRs, reflecting a relative lack of continental population structure, as a result of rapid mutation and genetic drift. Africa has higher GST values than does either Europe or Asia for all systems except the Y-chromosome STRs and Alus. All systems except the Y-chromosome STRs show less variation between populations within continents than between continents. These results are reassuring in their consistency and offer broad support for an African origin of modern human populations.\n" ], "offsets": [ [ 0, 1677 ] ] } ]

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[ { "id": "10677305__text", "type": "abstract", "text": [ "A new locus for autosomal recessive hypercholesterolemia maps to human chromosome 15q25-q26. High serum cholesterol is an established risk factor for cardiovascular disease and is the prime target for therapeutic intervention in large groups of patients. The development of modern treatments for this major risk factor was propelled by the early realization that forms of severe hypercholesterolemia could be caused by dominantly inherited defects in the LDL receptor or in the APOB gene. Further understanding of the mechanisms contributing to early atherosclerosis will allow for new targets for therapy. We therefore identified and investigated the genetics of families from Sardinia that have recessive inheritance of precocious hypercholesterolemia. We used five families in an analysis of linkage of the autosomal recessive hypercholesterolemia locus, termed \"ARH1,\" to chromosome 15q25-q26. A genomewide search mapped the disease-causing gene with a LOD score of 3.3 and excluded major contributions to the phenotype of other genes. A candidate gene present in the mapped chromosome region-the ligand-activated liver-transcription-factor gene ARP1 (apolipoprotein regulatory-protein gene)-has been excluded after DNA sequencing. The close-bred nature of the Sardinian population offers unique opportunities for isolation of this hypercholesterolemia-causing gene.\n" ], "offsets": [ [ 0, 1371 ] ] } ]

[ { "id": "10677305_T1", "type": "Gene", "text": [ "APOB" ], "offsets": [ [ 478, 482 ] ], "normalized": [] }, { "id": "10677305_T2", "type": "Gene", "text": [ "ARH1" ], "offsets": [ [ 866, 870 ] ], "normalized": [] }, { "id": "10677305_T3", "type": "Gene", "text": [ "ARP1" ], "offsets": [ [ 1150, 1154 ] ], "normalized": [] } ]

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[ { "id": "10884361__text", "type": "abstract", "text": [ "Statistical approaches to gene mapping.\n" ], "offsets": [ [ 0, 40 ] ] } ]

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[ { "id": "10677321__text", "type": "abstract", "text": [ "A coalescent approach to study linkage disequilibrium between single-nucleotide polymorphisms. We present the results of extensive simulations that emulate the development and distribution of linkage disequilibrium (LD) between single-nucleotide polymorphisms (SNPs) and a gene locus that is phenotypically stratified into two classes (disease phenotype and wild-type phenotype). Our approach, based on coalescence theory, allows an explicit modeling of the demographic history of the population without conditioning on the age of the mutation, and serves as an efficient tool to carry out simulations. More specifically, we compare the influence that a constant population size or an exponentially growing population has on the amount of LD. These results indicate that attempts to locate single disease genes are most likely successful in small and constant populations. On the other hand, if we consider an exponentially growing population that started to expand from an initially constant population of reasonable size, then our simulations indicate a lower success rate. The power to detect association is enhanced if haplotypes constructed from several SNPs are used as markers. The versatility of the coalescence approach also allows the analysis of other relevant factors that influence the chances that a disease gene will be located. We show that several alleles leading to the same disease have no substantial influence on the amount of LD, as long as the differences between the disease-causing alleles are confined to the same region of the gene locus and as long as each allele occurs in an appreciable frequency. Our simulations indicate that mapping of less-frequent diseases is more likely to be successful. Moreover, we show that successful attempts to map complex diseases depend crucially on the phenotype-genotype correlations of all alleles at the disease locus. An analysis of lipoprotein lipase data indicates that our simulations capture the major features of LD occurring in biological data.\n" ], "offsets": [ [ 0, 2018 ] ] } ]

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[ { "id": "10677322__text", "type": "abstract", "text": [ "Estimation of variance components of quantitative traits in inbred populations. Use of variance-component estimation for mapping of quantitative-trait loci in humans is a subject of great current interest. When only trait values, not genotypic information, are considered, variance-component estimation can also be used to estimate heritability of a quantitative trait. Inbred pedigrees present special challenges for variance-component estimation. First, there are more variance components to be estimated in the inbred case, even for a relatively simple model including additive, dominance, and environmental effects. Second, more identity coefficients need to be calculated from an inbred pedigree in order to perform the estimation, and these are computationally more difficult to obtain in the inbred than in the outbred case. As a result, inbreeding effects have generally been ignored in practice. We describe here the calculation of identity coefficients and estimation of variance components of quantitative traits in large inbred pedigrees, using the example of HDL in the Hutterites. We use a multivariate normal model for the genetic effects, extending the central-limit theorem of Lange to allow for both inbreeding and dominance under the assumptions of our variance-component model. We use simulated examples to give an indication of under what conditions one has the power to detect the additional variance components and to examine their impact on variance-component estimation. We discuss the implications for mapping and heritability estimation by use of variance components in inbred populations.\n" ], "offsets": [ [ 0, 1617 ] ] } ]

[ { "id": "10677322_T1", "type": "Gene", "text": [ "HDL" ], "offsets": [ [ 1072, 1075 ] ], "normalized": [] } ]

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[ { "id": "10739764__text", "type": "abstract", "text": [ "Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.\n" ], "offsets": [ [ 0, 1184 ] ] } ]

[ { "id": "10739764_T1", "type": "Gene", "text": [ "LMNA" ], "offsets": [ [ 27, 31 ] ], "normalized": [] }, { "id": "10739764_T2", "type": "Gene", "text": [ "LMNA," ], "offsets": [ [ 605, 610 ] ], "normalized": [] }, { "id": "10739764_T3", "type": "Gene", "text": [ "LMNA" ], "offsets": [ [ 733, 737 ] ], "normalized": [] } ]

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[ { "id": "10775530__text", "type": "abstract", "text": [ "Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. We report an unusual molecular defect in the mitochondrially encoded ND1 subunit of NADH ubiquinone oxidoreductase (complex I) in a patient with mitochondrial myopathy and isolated complex I deficiency. The mutation is an inversion of seven nucleotides within the ND1 gene, which maintains the reading frame. The inversion, which alters three highly conserved amino acids in the polypeptide, was heteroplasmic in the patient's muscle but was not detectable in blood. This is the first report of a pathogenic inversion mutation in human mtDNA.\n" ], "offsets": [ [ 0, 650 ] ] } ]

[ { "id": "10775530_T1", "type": "Gene", "text": [ "ND1" ], "offsets": [ [ 371, 374 ] ], "normalized": [] }, { "id": "10775530_T2", "type": "Gene", "text": [ "ND1" ], "offsets": [ [ 176, 179 ] ], "normalized": [] } ]

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[ { "id": "11078480__text", "type": "abstract", "text": [ "The extent of linkage disequilibrium in four populations with distinct demographic histories. The design and feasibility of whole-genome-association studies are critically dependent on the extent of linkage disequilibrium (LD) between markers. Although there has been extensive theoretical discussion of this, few empirical data exist. The authors have determined the extent of LD among 38 biallelic markers with minor allele frequencies >.1, since these are most comparable to the common disease-susceptibility polymorphisms that association studies aim to detect. The markers come from three chromosomal regions-1,335 kb on chromosome 13q12-13, 380 kb on chromosome 19q13.2, and 120 kb on chromosome 22q13.3-which have been extensively mapped. These markers were examined in approximately 1,600 individuals from four populations, all of European origin but with different demographic histories; Afrikaners, Ashkenazim, Finns, and East Anglian British. There are few differences, either in allele frequencies or in LD, among the populations studied. A similar inverse relationship was found between LD and distance in each genomic region and in each population. Mean D' is.68 for marker pairs <5 kb apart and is.24 for pairs separated by 10-20 kb, and the level of LD is not different from that seen in unlinked marker pairs separated by >500 kb. However, only 50% of marker pairs at distances <5 kb display sufficient LD (delta>.3) to be useful in association studies. Results of the present study, if representative of the whole genome, suggest that a whole-genome scan searching for common disease-susceptibility alleles would require markers spaced < or = 5 kb apart.\n" ], "offsets": [ [ 0, 1673 ] ] } ]

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[ { "id": "10631132__text", "type": "abstract", "text": [ "Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Fragile-X syndrome is a trinucleotide-repeat-expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 (FMR1) gene as the number of CGG repeats exceeds approximately 200. For premutation alleles ( approximately 55-200 repeats), no abnormalities in FMR1-gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55-192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase-PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with>100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.\n" ], "offsets": [ [ 0, 1649 ] ] } ]

[ { "id": "10631132_T1", "type": "Gene", "text": [ "FMR1" ], "offsets": [ [ 19, 23 ] ], "normalized": [] }, { "id": "10631132_T2", "type": "Gene", "text": [ "fragile-X mental retardation 1" ], "offsets": [ [ 261, 291 ] ], "normalized": [] }, { "id": "10631132_T3", "type": "Gene", "text": [ "FMR1" ], "offsets": [ [ 293, 297 ] ], "normalized": [] }, { "id": "10631132_T4", "type": "Gene", "text": [ "FMR1" ], "offsets": [ [ 437, 441 ] ], "normalized": [] }, { "id": "10631132_T5", "type": "Gene", "text": [ "FMR1" ], "offsets": [ [ 821, 825 ] ], "normalized": [] }, { "id": "10631132_T6", "type": "Gene", "text": [ "FMRP" ], "offsets": [ [ 835, 839 ] ], "normalized": [] }, { "id": "10631132_T7", "type": "Gene", "text": [ "FMR1" ], "offsets": [ [ 951, 955 ] ], "normalized": [] }, { "id": "10631132_T8", "type": "Gene", "text": [ "FMR1" ], "offsets": [ [ 1051, 1055 ] ], "normalized": [] }, { "id": "10631132_T9", "type": "Gene", "text": [ "FMR1" ], "offsets": [ [ 1626, 1630 ] ], "normalized": [] } ]

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[ { "id": "10631132_R1", "type": "Equals", "arg1_id": "10631132_T2", "arg2_id": "10631132_T3", "normalized": [] }, { "id": "10631132_R2", "type": "Equals", "arg1_id": "10631132_T4", "arg2_id": "10631132_T2", "normalized": [] }, { "id": "10631132_R3", "type": "Equals", "arg1_id": "10631132_T5", "arg2_id": "10631132_T6", "normalized": [] } ]

[ { "id": "11078473__text", "type": "abstract", "text": [ "The peopling of Europe from the maternal and paternal perspectives.\n" ], "offsets": [ [ 0, 68 ] ] } ]

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[ { "id": "11023809__text", "type": "abstract", "text": [ "Major genes regulating total serum immunoglobulin E levels in families with asthma. Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic disorders and asthma. Previous data from 92 families, each identified through a proband with asthma, showed evidence for two major genes regulating total serum IgE levels. One of these genes mapped to 5q31-33. In the current study, the segregation analysis was extended by the addition of 108 probands and their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitting and most-parsimonious one-locus model of the segregation analysis. A mixed two-major-gene model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-gene model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the first gene and homozygous low-risk allele at the second locus) had normal IgE levels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb had high IgE levels (mean 282 IU/ml). A genomewide screening was performed using variance-component analysis. Significant evidence for linkage was found for a novel locus at 7q, with a multipoint LOD score of 3. 36 (P=.00004). A LOD score of 3.65 (P=.00002) was obtained after genotyping additional markers in this region. Evidence for linkage was also found for two previously reported regions, 5q and 12q, with LOD scores of 2.73 (P=.0002) and 2.46 (P=.0004), respectively. These results suggest that several major genes, plus residual genetic effects, regulate total serum IgE levels.\n" ], "offsets": [ [ 0, 1721 ] ] } ]

[ { "id": "11023809_T1", "type": "Gene", "text": [ "IgE" ], "offsets": [ [ 102, 105 ] ], "normalized": [] }, { "id": "11023809_T2", "type": "Gene", "text": [ "Immunoglobulin E" ], "offsets": [ [ 84, 100 ] ], "normalized": [] }, { "id": "11023809_T3", "type": "Gene", "text": [ "IgE" ], "offsets": [ [ 316, 319 ] ], "normalized": [] }, { "id": "11023809_T4", "type": "Gene", "text": [ "IgE" ], "offsets": [ [ 1055, 1058 ] ], "normalized": [] }, { "id": "11023809_T5", "type": "Gene", "text": [ "IgE" ], "offsets": [ [ 1142, 1145 ] ], "normalized": [] }, { "id": "11023809_T6", "type": "Gene", "text": [ "IgE" ], "offsets": [ [ 1709, 1712 ] ], "normalized": [] } ]

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[ { "id": "11023809_R1", "type": "Equals", "arg1_id": "11023809_T2", "arg2_id": "11023809_T1", "normalized": [] } ]

[ { "id": "10762557__text", "type": "abstract", "text": [ "Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome.\n" ], "offsets": [ [ 0, 106 ] ] } ]

[ { "id": "10762557_T1", "type": "Gene", "text": [ "Complement factor H" ], "offsets": [ [ 0, 19 ] ], "normalized": [] } ]

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[ { "id": "10677310__text", "type": "abstract", "text": [ "Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis. Diffuse panbronchiolitis affecting East Asians is strongly associated with the class I human leukocyte antigen (HLA) alleles. Recent observations suggest that a major disease-susceptibility gene may be located between the HLA-B and HLA-A loci in the class I region of the major histocompatibility complex on chromosome 6. To test this possibility, we analyzed 14 polymorphic markers in 92 Japanese patients and 93 healthy controls. Of these, seven marker alleles, including HLA-B54 and HLA-A11, were significantly associated with the disease. Maximum-likelihood haplotype analysis and subsequent direct determination of individual haplotypes identified a group of disease-associated haplotypes, one of which contained all seven disease-associated marker alleles. Another haplotype, containing HLA-B*5504, was also associated with the disease. All these haplotypes seem to have diverged from a common ancestral haplotype in East Asians and share a specific segment containing three consecutive markers between the S and TFIIH loci in the class I region. Furthermore, one of the markers within the candidate region showed the highest delta value, indicating the strongest association. Of 20 Korean patients with diffuse panbronchiolitis, 17 also shared the combination of the disease-associated marker alleles within the candidate region. These results indicate that an HLA-associated major susceptibility gene for diffuse panbronchiolitis is probably located within the 200 kb in the class I region 300 kb telomeric of the HLA-B locus on the chromosome 6p21.3.\n" ], "offsets": [ [ 0, 1648 ] ] } ]

[ { "id": "10677310_T1", "type": "Gene", "text": [ "HLA" ], "offsets": [ [ 200, 203 ] ], "normalized": [] }, { "id": "10677310_T2", "type": "Gene", "text": [ "HLA-B" ], "offsets": [ [ 310, 315 ] ], "normalized": [] }, { "id": "10677310_T3", "type": "Gene", "text": [ "HLA-A" ], "offsets": [ [ 320, 325 ] ], "normalized": [] }, { "id": "10677310_T4", "type": "Gene", "text": [ "human leukocyte antigen" ], "offsets": [ [ 175, 198 ] ], "normalized": [] }, { "id": "10677310_T5", "type": "Gene", "text": [ "HLA-B54" ], "offsets": [ [ 562, 569 ] ], "normalized": [] }, { "id": "10677310_T6", "type": "Gene", "text": [ "HLA-A11," ], "offsets": [ [ 574, 582 ] ], "normalized": [] }, { "id": "10677310_T7", "type": "Gene", "text": [ "HLA-B*5504," ], "offsets": [ [ 881, 892 ] ], "normalized": [] }, { "id": "10677310_T8", "type": "Gene", "text": [ "TFIIH" ], "offsets": [ [ 1107, 1112 ] ], "normalized": [] }, { "id": "10677310_T9", "type": "Gene", "text": [ "HLA-B" ], "offsets": [ [ 1610, 1615 ] ], "normalized": [] } ]

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[ { "id": "10677310_R1", "type": "Equals", "arg1_id": "10677310_T4", "arg2_id": "10677310_T1", "normalized": [] } ]

[ { "id": "16826533__text", "type": "abstract", "text": [ "Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development.\n" ], "offsets": [ [ 0, 1083 ] ] } ]

[ { "id": "16826533_T1", "type": "Gene", "text": [ "WNT7A" ], "offsets": [ [ 13, 18 ] ], "normalized": [] }, { "id": "16826533_T2", "type": "Gene", "text": [ "dorsoventral-patterning" ], "offsets": [ [ 452, 475 ] ], "normalized": [] }, { "id": "16826533_T3", "type": "Gene", "text": [ "WNT7A" ], "offsets": [ [ 481, 486 ] ], "normalized": [] }, { "id": "16826533_T4", "type": "Gene", "text": [ "WNT7A" ], "offsets": [ [ 668, 673 ] ], "normalized": [] }, { "id": "16826533_T5", "type": "Gene", "text": [ "WNT7A" ], "offsets": [ [ 1025, 1030 ] ], "normalized": [] }, { "id": "16826533_T6", "type": "Gene", "text": [ "Wnt7a" ], "offsets": [ [ 742, 747 ] ], "normalized": [] } ]

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[ { "id": "16826533_R1", "type": "Equals", "arg1_id": "16826533_T2", "arg2_id": "16826533_T3", "normalized": [] } ]

[ { "id": "16358216__text", "type": "abstract", "text": [ "A novel framework for sib pair linkage analysis. Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs. To optimize power, various domain restrictions and null hypotheses have been proposed for each of these designs, yielding a wide array of choices for the analyst. To begin, we systematically classify the major sources of discretion in sib pair linkage analysis. Then, we extend the work of Kruglyak and Lander (1995), to bring the various forms into a unified framework and to facilitate a more general approach to the analysis. Finally, we describe a new, freely available computer program, Splat (Sib Pair Linkage Analysis Testing), that can perform any sib pair statistical test currently in use, as well as any user-defined test yet to be proposed. Splat uses the expectation maximization algorithm to calculate maximum-likelihood estimates of sharing (subject to user-specified conditions) and then plots LOD scores versus chromosomal position. It includes a novel grid-scanning capability that enables simultaneous visualization of multiple test statistics. This can lead to further insight into the genetic basis of the disease process under consideration. In addition, phenotype definitions can be modified without the recalculation of inheritance vectors, thereby providing considerable flexibility for exploratory analysis. The application of Splat will be illustrated with data from studies on the genetics of diabetic nephropathy.\n" ], "offsets": [ [ 0, 1932 ] ] } ]

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[ { "id": "16642433__text", "type": "abstract", "text": [ "Polymorphism in maternal LRP8 gene is associated with fetal growth. Fetal growth restriction (FGR) affects >200,000 pregnancies in the United States annually and is associated with increased perinatal mortality and morbidity, as well as poorer long-term health for infants with FGR compared with infants without FGR. FGR appears to be a complex trait, but the role of genetic factors in the development of FGR is largely unknown. We conducted a candidate-gene association study of birth weight and FGR in two independent study samples obtained at the Boston Medical Center. We first investigated the association between maternal genotypes of 68 single-nucleotide polymorphisms (SNPs) from 41 candidate genes and fetal growth in a sample of 204 black women selected for a previous study of preeclampsia, 92 of whom had preeclampsia (characterized by high blood pressure and the presence of protein in the urine). We found significant association between SNP rs2297660 in the LRP8 gene and birth weight. Subsequently, we replicated the association in a larger independent sample of 1,094 black women; similar association between LRP8 and FGR was observed in this sample. The \"A\" allele at rs2297660 was associated with a higher standardized birth weight and a lower risk of FGR. Under the additive genetic model, each additional copy of the \"A\" allele reduced the risk of FGR by 33% (P<.05). In conclusion, results from the two independent samples of black women provide consistent evidence that SNP rs2297660 in LRP8 is associated with fetal growth.\n" ], "offsets": [ [ 0, 1549 ] ] } ]

[ { "id": "16642433_T1", "type": "Gene", "text": [ "LRP8" ], "offsets": [ [ 25, 29 ] ], "normalized": [] }, { "id": "16642433_T2", "type": "Gene", "text": [ "LRP8" ], "offsets": [ [ 974, 978 ] ], "normalized": [] }, { "id": "16642433_T3", "type": "Gene", "text": [ "LRP8" ], "offsets": [ [ 1127, 1131 ] ], "normalized": [] }, { "id": "16642433_T4", "type": "Gene", "text": [ "LRP8" ], "offsets": [ [ 1511, 1515 ] ], "normalized": [] } ]

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[ { "id": "16358215__text", "type": "abstract", "text": [ "Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Hypophosphatemia due to isolated renal phosphate wasting results from a heterogeneous group of disorders. Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form that is characterized by reduced renal phosphate reabsorption, hypophosphatemia, and rickets. It can be distinguished from other forms of hypophosphatemia by increased serum levels of 1,25-dihydroxyvitamin D resulting in hypercalciuria. Using SNP array genotyping, we mapped the disease locus in two consanguineous families to the end of the long arm of chromosome 9. The candidate region contained a sodium-phosphate cotransporter gene, SLC34A3, which has been shown to be expressed in proximal tubulus cells. Sequencing of this gene revealed disease-associated mutations in five families, including two frameshift and one splice-site mutation. Loss of function of the SLC34A3 protein presumably results in a primary renal tubular defect and is compatible with the HHRH phenotype. We also show that the phosphaturic factor FGF23 (fibroblast growth factor 23), which is increased in X-linked hypophosphatemic rickets and carries activating mutations in autosomal dominant hypophosphatemic rickets, is at normal or low-normal serum levels in the patients with HHRH, further supporting a primary renal defect. Identification of the gene mutated in a further form of hypophosphatemia adds to the understanding of phosphate homeostasis and may help to elucidate the interaction of the proteins involved in this pathway.\n" ], "offsets": [ [ 0, 1647 ] ] } ]

[ { "id": "16358215_T1", "type": "Gene", "text": [ "SLC34A3" ], "offsets": [ [ 122, 129 ] ], "normalized": [] }, { "id": "16358215_T2", "type": "Gene", "text": [ "sodium-phosphate cotransporter" ], "offsets": [ [ 86, 116 ] ], "normalized": [] }, { "id": "16358215_T3", "type": "Gene", "text": [ "SLC34A3" ], "offsets": [ [ 769, 776 ] ], "normalized": [] }, { "id": "16358215_T4", "type": "Gene", "text": [ "SLC34A3" ], "offsets": [ [ 1001, 1008 ] ], "normalized": [] }, { "id": "16358215_T5", "type": "Gene", "text": [ "FGF23" ], "offsets": [ [ 1155, 1160 ] ], "normalized": [] }, { "id": "16358215_T6", "type": "Gene", "text": [ "fibroblast growth factor 23" ], "offsets": [ [ 1162, 1189 ] ], "normalized": [] } ]

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[ { "id": "16358215_R1", "type": "Equals", "arg1_id": "16358215_T2", "arg2_id": "16358215_T1", "normalized": [] }, { "id": "16358215_R2", "type": "Equals", "arg1_id": "16358215_T5", "arg2_id": "16358215_T6", "normalized": [] } ]

[ { "id": "16642431__text", "type": "abstract", "text": [ "Fine-mapping chromosome 20 in 230 systemic lupus erythematosus sib pair and multiplex families: evidence for genetic epistasis with chromosome 16q12. The presence of systemic lupus erythematosus (SLE) susceptibility genes on chromosome 20 is suggested by the observation of genetic linkage in several independent SLE family collections. To further localize the genetic effects, we typed 59 microsatellites in the two best regions, as defined by genome screens. Genotypes were analyzed for statistical linkage and/or association with SLE, by use of a combination of nonparametric linkage methods, family-based tests of association (transmission/disequilibrium and pedigree disequilibrium tests), and haplotype-sharing statistics (haplotype runs test), in a set of 230 SLE pedigrees. Maximal evidence for linkage to SLE was to 20p12 (LOD = 2.84) and 20q13.1 (LOD = 1.64) in the white pedigrees. Subsetting families on the basis of evidence for linkage to 16q12 significantly improved the LOD scores at both chromosome 20 locations (20p12 LOD = 5.06 and 20q13 LOD = 3.65), consistent with epistasis. We then typed 162 single-nucleotide polymorphism markers across a 1.3-Mb candidate region on 20q13.1 and identified several SNPs that demonstrated significant evidence for association. These data provide additional support for linkage and association to 20p12 and 20q13.1 in SLE and further refine the intervals of interest. These data further suggest the possibility of epistatic relationships among loci within the 20q12, 20q13, and 16q12 regions in SLE families.\n" ], "offsets": [ [ 0, 1563 ] ] } ]

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[ { "id": "16960802__text", "type": "abstract", "text": [ "Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness. Mutations in genes encoding either components of the phototransduction cascade or proteins presumably involved in signaling from photoreceptors to adjacent second-order neurons have been shown to cause congenital stationary night blindness (CSNB). Sequence alterations in CACNA1F lead to the incomplete type of CSNB (CSNB2), which can be distinguished by standard electroretinography (ERG). CSNB2 is associated with a reduced rod b-wave, a substantially reduced cone a-wave, and a reduced 30-Hz flicker ERG response. CACNA1F encodes the alpha 1-subunit of an L-type Ca2+ channel (Cav1.4 alpha ), which is specific to photoreceptors and is present at high density in the synaptic terminals. Ten of our patients with CSNB2 showed no mutation in CACNA1F. To identify the disease-causing mutations, we used a candidate-gene approach. CABP4, a member of the calcium-binding protein (CABP) family, is located in photoreceptor synaptic terminals and is directly associated with the C-terminal domain of the Cav1.4 alpha . Mice lacking either Cabp4 or Cav1.4 alpha display a CSNB2-like phenotype. Here, we report for the first time that mutations in CABP4 lead to autosomal recessive CSNB. Our studies revealed homozygous and compound heterozygous mutations in two families. We also show that these mutations reduce the transcript levels to 30%-40% of those in controls. This suggests that the reduced amount of CABP4 is the reason for the signaling defect in these patients.\n" ], "offsets": [ [ 0, 1577 ] ] } ]

[ { "id": "16960802_T1", "type": "Gene", "text": [ "CABP4" ], "offsets": [ [ 13, 18 ] ], "normalized": [] }, { "id": "16960802_T2", "type": "Gene", "text": [ "Ca2+-binding protein 4" ], "offsets": [ [ 42, 64 ] ], "normalized": [] }, { "id": "16960802_T3", "type": "Gene", "text": [ "CACNA1F" ], "offsets": [ [ 381, 388 ] ], "normalized": [] }, { "id": "16960802_T7", "type": "Gene", "text": [ "CACNA1F" ], "offsets": [ [ 626, 633 ] ], "normalized": [] }, { "id": "16960802_T8", "type": "Gene", "text": [ "Cav1.4 alpha" ], "offsets": [ [ 689, 701 ] ], "normalized": [] }, { "id": "16960802_T4", "type": "Gene", "text": [ "CACNA1F" ], "offsets": [ [ 852, 859 ] ], "normalized": [] }, { "id": "16960802_T5", "type": "Gene", "text": [ "CABP4" ], "offsets": [ [ 939, 944 ] ], "normalized": [] }, { "id": "16960802_T6", "type": "Gene", "text": [ "Cav1.4 alpha" ], "offsets": [ [ 1109, 1121 ] ], "normalized": [] }, { "id": "16960802_T9", "type": "Gene", "text": [ "Cabp4" ], "offsets": [ [ 1144, 1149 ] ], "normalized": [] }, { "id": "16960802_T10", "type": "Gene", "text": [ "Cav1.4 alpha" ], "offsets": [ [ 1153, 1165 ] ], "normalized": [] }, { "id": "16960802_T11", "type": "Gene", "text": [ "CABP4" ], "offsets": [ [ 1251, 1256 ] ], "normalized": [] }, { "id": "16960802_T12", "type": "Gene", "text": [ "CABP4" ], "offsets": [ [ 1513, 1518 ] ], "normalized": [] } ]

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[ { "id": "16960802_R1", "type": "Equals", "arg1_id": "16960802_T1", "arg2_id": "16960802_T2", "normalized": [] }, { "id": "16960802_R2", "type": "Equals", "arg1_id": "16960802_T7", "arg2_id": "16960802_T8", "normalized": [] } ]

[ { "id": "16773577__text", "type": "abstract", "text": [ "Familial osteoarthritis of the hip joint associated with acetabular dysplasia maps to chromosome 13q. Genetic factors have been implicated in osteoarthritis (OA), particularly in OA of the hip joint (hip OA). Several instances of familial hip OA that show distinctive modes of inheritance but that differ from chondrodysplasia have been reported. Here, we report the characterization of a large Japanese family with an inherited disease of the hip that is indistinguishable from common hip OA, as evidenced by clinical symptoms and radiographs of the joint. This family contained eight patients in 4 generations. Affected individuals develop pain in the hip joint during adolescence, and the disease progresses to severe crippling before age 60 years. Patients generally are in good health, height is not reduced, and there is no extraskeletal involvement suggestive of chondrodysplasia. The skeletal change is bilateral acetabular dysplasia followed by OA, which occurs after age approximately 40 years and is indistinguishable from idiopathic nonfamilial dysplastic hip OA. This trait shows autosomal dominant inheritance, with a considerably consistent phenotype. Genomewide screening revealed linkage at chromosome 13q22, and haplotype analysis narrowed the locus to a 6.0-cM interval between markers D13S1296 and D13S162, with a maximal multipoint LOD score of 3.57. The family described here represents a novel genetic entity as a monogenic form of hip OA. Its further characterization can aid in elucidating the etiology and pathogenesis of a common idiopathic form of OA.\n" ], "offsets": [ [ 0, 1580 ] ] } ]

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[ { "id": "16642441__text", "type": "abstract", "text": [ "Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community. Several lines of evidence support for a role of angiotensin converting enzyme (ACE) in Alzheimer disease (AD). Most genetic studies have focused on an Alu insertion/deletion (I/D) polymorphism in the ACE gene (DCP1) and have yielded conflicting results. We evaluated the association between 15 single-nucleotide polymorphisms (SNPs) in DCP1, including the I/D variant, and AD in a sample of 92 patients with AD and 166 nondemented controls from an inbred Israeli Arab community. Although there was no evidence for association between AD and I/D, we observed significant association with SNPs rs4343 (P = .00001) and rs4351 (P = .01). Haplotype analysis revealed remarkably significant evidence of association with the SNP combination rs4343 and rs4351 (global P = 7.5 x 10(-7)). Individuals possessing the haplotype \"GA\" (frequency 0.21 in cases and 0.01 in controls) derived from these SNPs had a 45-fold increased risk of developing AD (95% CI 6.0-343.2) compared with those possessing any of the other three haplotypes. Longer range haplotypes including I/D were even more significant (lowest global P = 1.1 x 10(-12)), but the only consistently associated alleles were in rs4343 and rs4351. These results suggest that a variant in close proximity to rs4343 and rs4351 modulates susceptibility to AD in this community.\n" ], "offsets": [ [ 0, 1446 ] ] } ]

[ { "id": "16642441_T1", "type": "Gene", "text": [ "Angiotensin-converting enzyme" ], "offsets": [ [ 36, 65 ] ], "normalized": [] }, { "id": "16642441_T2", "type": "Gene", "text": [ "angiotensin converting enzyme" ], "offsets": [ [ 172, 201 ] ], "normalized": [] }, { "id": "16642441_T3", "type": "Gene", "text": [ "ACE" ], "offsets": [ [ 203, 206 ] ], "normalized": [] }, { "id": "16642441_T4", "type": "Gene", "text": [ "ACE" ], "offsets": [ [ 324, 327 ] ], "normalized": [] }, { "id": "16642441_T5", "type": "Gene", "text": [ "DCP1" ], "offsets": [ [ 334, 338 ] ], "normalized": [] }, { "id": "16642441_T6", "type": "Gene", "text": [ "DCP1" ], "offsets": [ [ 460, 464 ] ], "normalized": [] } ]

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[ { "id": "16642441_R1", "type": "Equals", "arg1_id": "16642441_T2", "arg2_id": "16642441_T3", "normalized": [] } ]

[ { "id": "16909394__text", "type": "abstract", "text": [ "Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A-->G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.\n" ], "offsets": [ [ 0, 875 ] ] } ]

[ { "id": "16909394_T1", "type": "Gene", "text": [ "CEP290" ], "offsets": [ [ 17, 23 ] ], "normalized": [] }, { "id": "16909394_T2", "type": "Gene", "text": [ "NPHP6" ], "offsets": [ [ 25, 30 ] ], "normalized": [] }, { "id": "16909394_T3", "type": "Gene", "text": [ "CEP290" ], "offsets": [ [ 443, 449 ] ], "normalized": [] }, { "id": "16909394_T4", "type": "SNP", "text": [ "c.2991+1655A-->G" ], "offsets": [ [ 498, 514 ] ], "normalized": [] }, { "id": "16909394_T5", "type": "Gene", "text": [ "CEP290" ], "offsets": [ [ 590, 596 ] ], "normalized": [] }, { "id": "16909394_T6", "type": "Gene", "text": [ "CEP290" ], "offsets": [ [ 780, 786 ] ], "normalized": [] } ]

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[ { "id": "16909394_R1", "type": "Equals", "arg1_id": "16909394_T1", "arg2_id": "16909394_T2", "normalized": [] }, { "id": "16909394_R2", "type": "AssociatedTo", "arg1_id": "16909394_T4", "arg2_id": "16909394_T5", "normalized": [] } ]

[ { "id": "16909392__text", "type": "abstract", "text": [ "Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. Navajo neurohepatopathy (NNH) is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance. Homozygosity mapping of two families with NNH suggested linkage to chromosome 2p24. This locus includes the MPV17 gene, which, when mutated, causes a hepatocerebral form of mtDNA depletion. Sequencing of the MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q mutation described elsewhere. Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations.\n" ], "offsets": [ [ 0, 1154 ] ] } ]

[ { "id": "16909392_T1", "type": "Gene", "text": [ "MPV17" ], "offsets": [ [ 55, 60 ] ], "normalized": [] }, { "id": "16909392_T2", "type": "Gene", "text": [ "MPV17" ], "offsets": [ [ 743, 748 ] ], "normalized": [] }, { "id": "16909392_T3", "type": "SNP", "text": [ "R50Q" ], "offsets": [ [ 922, 926 ] ], "normalized": [] }, { "id": "16909392_T4", "type": "Gene", "text": [ "MPV17" ], "offsets": [ [ 843, 848 ] ], "normalized": [] }, { "id": "16909392_T5", "type": "Gene", "text": [ "MPV17" ], "offsets": [ [ 1137, 1142 ] ], "normalized": [] } ]

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[ { "id": "16909392_R1", "type": "AssociatedTo", "arg1_id": "16909392_T3", "arg2_id": "16909392_T4", "normalized": [] } ]

[ { "id": "16960800__text", "type": "abstract", "text": [ "A genomewide single-nucleotide-polymorphism panel with high ancestry information for African American admixture mapping. Admixture mapping requires a genomewide panel of relatively evenly spaced markers that can distinguish the ancestral origins of chromosomal segments in admixed individuals. Through use of the results of the International HapMap Project and specific selection criteria, the current study has examined the ability of selected single-nucleotide polymorphisms (SNPs) to extract continental ancestry information in African American subjects and to explore parameters for admixture mapping. Genotyping of two linguistically diverse West African populations (Bini and Kanuri Nigerians, who are Niger-Congo [Bantu] and Nilo-Saharan speakers, respectively), European Americans, and African Americans validated a genomewide set of >4,000 SNP ancestry-informative markers with mean and median F(ST) values >0.59 and mean and median Fisher's information content >2.5. This set of SNPs extracted a larger amount of ancestry information in African Americans than previously reported SNP panels and provides nearly uniform coverage of the genome. Moreover, in the current study, simulations show that this more informative panel improves power for admixture mapping in African Americans when ethnicity risk ratios are modest. This is particularly important in the application of admixture mapping in complex genetic diseases for which only modest ethnicity risk ratios of relevant susceptibility genes are expected.\n" ], "offsets": [ [ 0, 1522 ] ] } ]

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[ { "id": "16642442__text", "type": "abstract", "text": [ "Breakpoint cloning and haplotype analysis indicate a single origin of the common Inv(10)(p11.2q21.2) mutation among northern Europeans. The pericentric inv(10)(p11.2q21.2) mutation has been frequently identified in cytogenetic laboratories, is phenotypically silent, and is considered to be a polymorphic variant. Cloning and sequencing of the junction fragments on 10p11 and 10q21 revealed that neither inversion breakpoint directly involved any genes or repetitive sequences, although both breakpoint regions contain a number of repeats. All 20 apparently unrelated inv(10) families in our study had identical breakpoints, and detailed haplotype analysis showed that the inversions were identical by descent. Thus, although considered a common variant, inv(10)(p11.2q21.2) has a single ancestral founder among northern Europeans.\n" ], "offsets": [ [ 0, 832 ] ] } ]

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[ { "id": "16532386__text", "type": "abstract", "text": [ "Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus. We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders--including social phobia, agoraphobia, and simple phobia--in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P<.05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.\n" ], "offsets": [ [ 0, 2089 ] ] } ]

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[ { "id": "16532386_R1", "type": "Equals", "arg1_id": "16532386_T1", "arg2_id": "16532386_T2", "normalized": [] } ]

[ { "id": "16532395__text", "type": "abstract", "text": [ "Spread of an inactive form of caspase-12 in humans is due to recent positive selection. The human caspase-12 gene is polymorphic for the presence or absence of a stop codon, which results in the occurrence of both active (ancestral) and inactive (derived) forms of the gene in the population. It has been shown elsewhere that carriers of the inactive gene are more resistant to severe sepsis. We have now investigated whether the inactive form has spread because of neutral drift or positive selection. We determined its distribution in a worldwide sample of 52 populations and resequenced the gene in 77 individuals from the HapMap Yoruba, Han Chinese, and European populations. There is strong evidence of positive selection from low diversity, skewed allele-frequency spectra, and the predominance of a single haplotype. We suggest that the inactive form of the gene arose in Africa approximately 100-500 thousand years ago (KYA) and was initially neutral or almost neutral but that positive selection beginning approximately 60-100 KYA drove it to near fixation. We further propose that its selective advantage was sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased.\n" ], "offsets": [ [ 0, 1239 ] ] } ]

[ { "id": "16532395_T1", "type": "Gene", "text": [ "caspase-12" ], "offsets": [ [ 98, 108 ] ], "normalized": [] }, { "id": "16532395_T2", "type": "Gene", "text": [ "caspase-12" ], "offsets": [ [ 30, 40 ] ], "normalized": [] } ]

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[ { "id": "16826523__text", "type": "abstract", "text": [ "Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. Genomic imbalance is a common cause of phenotypic abnormalities. We measured the relative expression level of genes that map within the microdeletion that causes Williams-Beuren syndrome and within its flanking regions. We found, unexpectedly, that not only hemizygous genes but also normal-copy neighboring genes show decreased relative levels of expression. Our results suggest that not only the aneuploid genes but also the flanking genes that map several megabases away from a genomic rearrangement should be considered possible contributors to the phenotypic variation in genomic disorders.\n" ], "offsets": [ [ 0, 728 ] ] } ]

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[ { "id": "17186465__text", "type": "abstract", "text": [ "Exact tests of Hardy-Weinberg equilibrium and homogeneity of disequilibrium across strata. Detecting departures from Hardy-Weinberg equilibrium (HWE) of marker-genotype frequencies is a crucial first step in almost all human genetic analyses. When a sample is stratified by multiple ethnic groups, it is important to allow the marker-allele frequencies to differ over the strata. In this situation, it is common to test for HWE by using an exact test within each stratum and then using the minimum P value as a global test. This approach does not account for multiple testing, and, because it does not combine information over strata, it does not have optimal power. Several approximate methods to combine information over strata have been proposed, but most of them sum over strata a measure of departure from HWE; if the departures are in different directions, then summing can diminish the overall evidence of departure from HWE. An exact stratified test is more appealing because it uses the probability of genotype configurations across the strata as evidence for global departures from HWE. We developed an exact stratified test for HWE for diallelic markers, such as single-nucleotide polymorphisms (SNPs), and an exact test for homogeneity of Hardy-Weinberg disequilibrium. By applying our methods to data from Perlegen and HapMap--a combined total of more than five million SNP genotypes, with three to four strata and strata sizes ranging from 23 to 60 subjects--we illustrate that the exact stratified test provides more-robust and more-powerful results than those obtained by either the minimum of exact test P values over strata or approximate stratified tests that sum measures of departure from HWE. Hence, our new methods should be useful for samples composed of multiple ethnic groups.\n" ], "offsets": [ [ 0, 1803 ] ] } ]

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[ { "id": "16960803__text", "type": "abstract", "text": [ "Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development. The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous--along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.\n" ], "offsets": [ [ 0, 1755 ] ] } ]

[ { "id": "16960803_T1", "type": "Gene", "text": [ "Satb2" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "16960803_T2", "type": "Gene", "text": [ "SATB2" ], "offsets": [ [ 167, 172 ] ], "normalized": [] }, { "id": "16960803_T3", "type": "Gene", "text": [ "Satb2" ], "offsets": [ [ 485, 490 ] ], "normalized": [] }, { "id": "16960803_T4", "type": "Gene", "text": [ "SATB2" ], "offsets": [ [ 534, 539 ] ], "normalized": [] }, { "id": "16960803_T5", "type": "Gene", "text": [ "Satb2" ], "offsets": [ [ 621, 626 ] ], "normalized": [] }, { "id": "16960803_T6", "type": "Gene", "text": [ "Satb2" ], "offsets": [ [ 783, 788 ] ], "normalized": [] }, { "id": "16960803_T7", "type": "Gene", "text": [ "Satb2" ], "offsets": [ [ 906, 911 ] ], "normalized": [] }, { "id": "16960803_T8", "type": "Gene", "text": [ "Pax9" ], "offsets": [ [ 1069, 1073 ] ], "normalized": [] }, { "id": "16960803_T9", "type": "Gene", "text": [ "Alx4" ], "offsets": [ [ 1075, 1079 ] ], "normalized": [] }, { "id": "16960803_T10", "type": "Gene", "text": [ "Msx1" ], "offsets": [ [ 1085, 1089 ] ], "normalized": [] }, { "id": "16960803_T11", "type": "Gene", "text": [ "Satb2/SATB2" ], "offsets": [ [ 1300, 1311 ] ], "normalized": [] }, { "id": "16960803_T12", "type": "Gene", "text": [ "Satb2" ], "offsets": [ [ 1486, 1491 ] ], "normalized": [] } ]

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[ { "id": "16960810__text", "type": "abstract", "text": [ "Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Systemic lupus erythematosus is a prototypic autoimmune disease. Apart from rare monogenic deficiencies of complement factors, where lupuslike disease may occur in association with other autoimmune diseases or high susceptibility to bacterial infections, its etiology is multifactorial in nature. Cutaneous findings are a hallmark of the disease and manifest either alone or in association with internal-organ disease. We describe a novel genodermatosis characterized by painful bluish-red inflammatory papular or nodular lesions in acral locations such as fingers, toes, nose, cheeks, and ears. The lesions sometimes appear plaquelike and tend to ulcerate. Manifestation usually begins in early childhood and is precipitated by cold and wet exposure. Apart from arthralgias, there is no evidence for internal-organ disease or an increased susceptibility to infection. Histological findings include a deep inflammatory infiltrate with perivascular distribution and granular deposits of immunoglobulins and complement along the basement membrane. Some affected individuals show antinuclear antibodies or immune complex formation, whereas cryoglobulins or cold agglutinins are absent. Thus, the findings are consistent with chilblain lupus, a rare form of cutaneous lupus erythematosus. Investigation of a large German kindred with 18 affected members suggests a highly penetrant trait with autosomal dominant inheritance. By single-nucleotide-polymorphism-based genomewide linkage analysis, the locus was mapped to chromosome 3p. Haplotype analysis defined the locus to a 13.8-cM interval with a LOD score of 5.04. This is the first description of a monogenic form of cutaneous lupus erythematosus. Identification of the gene responsible for familial chilblain lupus may shed light on the pathogenesis of common forms of connective-tissue disease such as systemic lupus erythematosus.\n" ], "offsets": [ [ 0, 1984 ] ] } ]

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[ { "id": "16909383__text", "type": "abstract", "text": [ "A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.\n" ], "offsets": [ [ 0, 1983 ] ] } ]

[ { "id": "16909383_T1", "type": "Gene", "text": [ "COL9A1" ], "offsets": [ [ 83, 89 ] ], "normalized": [] }, { "id": "16909383_T2", "type": "Gene", "text": [ "COL2A1" ], "offsets": [ [ 276, 282 ] ], "normalized": [] }, { "id": "16909383_T3", "type": "Gene", "text": [ "COL11A1" ], "offsets": [ [ 284, 291 ] ], "normalized": [] }, { "id": "16909383_T4", "type": "Gene", "text": [ "COL11A2" ], "offsets": [ [ 297, 304 ] ], "normalized": [] }, { "id": "16909383_T5", "type": "Gene", "text": [ "COL9A1" ], "offsets": [ [ 834, 840 ] ], "normalized": [] }, { "id": "16909383_T6", "type": "Gene", "text": [ "COL9A1" ], "offsets": [ [ 1105, 1111 ] ], "normalized": [] }, { "id": "16909383_T7", "type": "SNP", "text": [ "R295X" ], "offsets": [ [ 1137, 1142 ] ], "normalized": [] }, { "id": "16909383_T8", "type": "SNP", "text": [ "R295X" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] }, { "id": "16909383_T9", "type": "SNP", "text": [ "R295X" ], "offsets": [ [ 1389, 1394 ] ], "normalized": [] }, { "id": "16909383_T10", "type": "Gene", "text": [ "COL9A1" ], "offsets": [ [ 1451, 1457 ] ], "normalized": [] } ]

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[ { "id": "16909383_R1", "type": "AssociatedTo", "arg1_id": "16909383_T7", "arg2_id": "16909383_T6", "normalized": [] } ]

[ { "id": "16773567__text", "type": "abstract", "text": [ "Intra- and interindividual epigenetic variation in human germ cells. Epigenetics represents a secondary inheritance system that has been poorly investigated in human biology. The objective of this study was to perform a comprehensive analysis of DNA methylation variation between and within the germlines of normal males. First, methylated cytosines were mapped using bisulphite modification-based sequencing in the promoter regions of the following disease genes: presenilins (PSEN1 and PSEN2), breast cancer (BRCA1 and BRCA2), myotonic dystrophy (DM1), and Huntington disease (HD). Major epigenetic variation was detected within samples, since the majority of sperm cells of the same individual exhibited unique DNA methylation profiles. In the interindividual analysis, 41 of 61 pairwise comparisons revealed distinct DNA methylation profiles (P=.036 to 6.8 x 10(-14)). Second, a microarray-based epigenetic profiling of the same sperm samples was performed using a 12,198-feature CpG island microarray. The microarray analysis has identified numerous DNA methylation-variable positions in the germ cell genome. The largest degree of variation was detected within the promoter CpG islands and pericentromeric satellites among the single-copy DNA fragments and repetitive elements, respectively. A number of genes, such as EED, CTNNA2, CALM1, CDH13, and STMN2, exhibited age-related DNA methylation changes. Finally, allele-specific methylation patterns in CDH13 were detected. This study provides evidence for significant epigenetic variability in human germ cells, which warrants further research to determine whether such epigenetic patterns can be efficiently transmitted across generations and what impact inherited epigenetic individuality may have on phenotypic outcomes in health and disease.\n" ], "offsets": [ [ 0, 1803 ] ] } ]

[ { "id": "16773567_T1", "type": "Gene", "text": [ "PSEN1" ], "offsets": [ [ 478, 483 ] ], "normalized": [] }, { "id": "16773567_T2", "type": "Gene", "text": [ "PSEN2" ], "offsets": [ [ 488, 493 ] ], "normalized": [] }, { "id": "16773567_T3", "type": "Gene", "text": [ "BRCA1" ], "offsets": [ [ 511, 516 ] ], "normalized": [] }, { "id": "16773567_T4", "type": "Gene", "text": [ "BRCA2" ], "offsets": [ [ 521, 526 ] ], "normalized": [] }, { "id": "16773567_T5", "type": "Gene", "text": [ "DM1" ], "offsets": [ [ 549, 552 ] ], "normalized": [] }, { "id": "16773567_T7", "type": "Gene", "text": [ "EED" ], "offsets": [ [ 1325, 1328 ] ], "normalized": [] }, { "id": "16773567_T8", "type": "Gene", "text": [ "CTNNA2" ], "offsets": [ [ 1330, 1336 ] ], "normalized": [] }, { "id": "16773567_T9", "type": "Gene", "text": [ "CALM1" ], "offsets": [ [ 1338, 1343 ] ], "normalized": [] }, { "id": "16773567_T10", "type": "Gene", "text": [ "CDH13" ], "offsets": [ [ 1345, 1350 ] ], "normalized": [] }, { "id": "16773567_T11", "type": "Gene", "text": [ "STMN2" ], "offsets": [ [ 1356, 1361 ] ], "normalized": [] }, { "id": "16773567_T12", "type": "Gene", "text": [ "CDH13" ], "offsets": [ [ 1459, 1464 ] ], "normalized": [] }, { "id": "16773567_T6", "type": "Gene", "text": [ "HD" ], "offsets": [ [ 579, 581 ] ], "normalized": [] } ]

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[ { "id": "23084292__text", "type": "abstract", "text": [ "Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans. We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).\n" ], "offsets": [ [ 0, 1499 ] ] } ]

[ { "id": "23084292_T1", "type": "Gene", "text": [ "HLA-DRB1" ], "offsets": [ [ 875, 883 ] ], "normalized": [] }, { "id": "23084292_T2", "type": "Gene", "text": [ "HLA-DRB1" ], "offsets": [ [ 893, 901 ] ], "normalized": [] }, { "id": "23084292_T3", "type": "Gene", "text": [ "HLA-DQA1" ], "offsets": [ [ 915, 923 ] ], "normalized": [] }, { "id": "23084292_T4", "type": "Gene", "text": [ "NOTCH4" ], "offsets": [ [ 987, 993 ] ], "normalized": [] }, { "id": "23084292_T5", "type": "Gene", "text": [ "MICB" ], "offsets": [ [ 1010, 1014 ] ], "normalized": [] }, { "id": "23084292_T6", "type": "Gene", "text": [ "HLA-DRB1" ], "offsets": [ [ 1138, 1146 ] ], "normalized": [] } ]

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[ { "id": "22444671__text", "type": "abstract", "text": [ "Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome. CHIME syndrome is characterized by colobomas, heart defects, ichthyosiform dermatosis, mental retardation (intellectual disability), and ear anomalies, including conductive hearing loss. Whole-exome sequencing on five previously reported cases identified PIGL, the de-N-acetylase required for glycosylphosphatidylinositol (GPI) anchor formation, as a strong candidate. Furthermore, cell lines derived from these cases had significantly reduced levels of the two GPI anchor markers, CD59 and a GPI-binding toxin, aerolysin (FLAER), confirming the pathogenicity of the mutations.\n" ], "offsets": [ [ 0, 656 ] ] } ]

[ { "id": "22444671_T1", "type": "Gene", "text": [ "PIGL" ], "offsets": [ [ 51, 55 ] ], "normalized": [] }, { "id": "22444671_T2", "type": "Gene", "text": [ "glycosylphosphatidylinositol" ], "offsets": [ [ 17, 45 ] ], "normalized": [] }, { "id": "22444671_T3", "type": "Gene", "text": [ "PIGL" ], "offsets": [ [ 333, 337 ] ], "normalized": [] }, { "id": "22444671_T4", "type": "Gene", "text": [ "CD59" ], "offsets": [ [ 560, 564 ] ], "normalized": [] } ]

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[ { "id": "22444671_R1", "type": "Equals", "arg1_id": "22444671_T2", "arg2_id": "22444671_T1", "normalized": [] } ]

[ { "id": "22503632__text", "type": "abstract", "text": [ "SHANK1 Deletions in Males with Autism Spectrum Disorder. Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.\n" ], "offsets": [ [ 0, 1453 ] ] } ]

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[ { "id": "23122590__text", "type": "abstract", "text": [ "Linkage-disequilibrium-based binning misleads the interpretation of genome-wide association studies.\n" ], "offsets": [ [ 0, 101 ] ] } ]

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[ { "id": "22265016__text", "type": "abstract", "text": [ "RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.\n" ], "offsets": [ [ 0, 1437 ] ] } ]

[ { "id": "22265016_T1", "type": "Gene", "text": [ "RHBDF2" ], "offsets": [ [ 0, 6 ] ], "normalized": [] }, { "id": "22265016_T2", "type": "SNP", "text": [ "c.557T>C" ], "offsets": [ [ 475, 483 ] ], "normalized": [] }, { "id": "22265016_T3", "type": "SNP", "text": [ "c.566C>T" ], "offsets": [ [ 502, 510 ] ], "normalized": [] }, { "id": "22265016_T4", "type": "SNP", "text": [ "p.Ile186Thr" ], "offsets": [ [ 485, 496 ] ], "normalized": [] }, { "id": "22265016_T5", "type": "SNP", "text": [ "p.Pro189Leu" ], "offsets": [ [ 512, 523 ] ], "normalized": [] }, { "id": "22265016_T6", "type": "Gene", "text": [ "RHBDF2" ], "offsets": [ [ 528, 534 ] ], "normalized": [] }, { "id": "22265016_T7", "type": "Gene", "text": [ "RHBDF2" ], "offsets": [ [ 581, 587 ] ], "normalized": [] }, { "id": "22265016_T8", "type": "Gene", "text": [ "iRhom2" ], "offsets": [ [ 603, 609 ] ], "normalized": [] }, { "id": "22265016_T9", "type": "Gene", "text": [ "RHBDF2" ], "offsets": [ [ 677, 683 ] ], "normalized": [] }, { "id": "22265016_T10", "type": "Gene", "text": [ "EGFR" ], "offsets": [ [ 855, 859 ] ], "normalized": [] }, { "id": "22265016_T11", "type": "Gene", "text": [ "epidermal growth factor receptor" ], "offsets": [ [ 821, 853 ] ], "normalized": [] }, { "id": "22265016_T12", "type": "Gene", "text": [ "EGFR" ], "offsets": [ [ 1054, 1058 ] ], "normalized": [] }, { "id": "22265016_T13", "type": "Gene", "text": [ "RHBDF2" ], "offsets": [ [ 1156, 1162 ] ], "normalized": [] }, { "id": "22265016_T14", "type": "Gene", "text": [ "RHBDF2" ], "offsets": [ [ 1249, 1255 ] ], "normalized": [] } ]

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[ { "id": "23159251__text", "type": "abstract", "text": [ "An exponential combination procedure for set-based association tests in sequencing studies. State-of-the-art next-generation-sequencing technologies can facilitate in-depth explorations of the human genome by investigating both common and rare variants. For the identification of genetic factors that are associated with disease risk or other complex phenotypes, methods have been proposed for jointly analyzing variants in a set (e.g., all coding SNPs in a gene). Variants in a properly defined set could be associated with risk or phenotype in a concerted fashion, and by accumulating information from them, one can improve power to detect genetic risk factors. Many set-based methods in the literature are based on statistics that can be written as the summation of variant statistics. Here, we propose taking the summation of the exponential of variant statistics as the set summary for association testing. From both Bayesian and frequentist perspectives, we provide theoretical justification for taking the sum of the exponential of variant statistics because it is particularly powerful for sparse alternatives-that is, compared with the large number of variants being tested in a set, only relatively few variants are associated with disease risk-a distinctive feature of genetic data. We applied the exponential combination gene-based test to a sequencing study in anticancer pharmacogenomics and uncovered mechanistic insights into genes and pathways related to chemotherapeutic susceptibility for an important class of oncologic drugs.\n" ], "offsets": [ [ 0, 1547 ] ] } ]

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[ { "id": "22795537__text", "type": "abstract", "text": [ "De novo mutations in MLL cause Wiedemann-Steiner syndrome. Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.\n" ], "offsets": [ [ 0, 1231 ] ] } ]

[ { "id": "22795537_T1", "type": "Gene", "text": [ "MLL" ], "offsets": [ [ 21, 24 ] ], "normalized": [] }, { "id": "22795537_T2", "type": "Gene", "text": [ "MLL" ], "offsets": [ [ 557, 560 ] ], "normalized": [] }, { "id": "22795537_T3", "type": "Gene", "text": [ "MLL" ], "offsets": [ [ 593, 596 ] ], "normalized": [] } ]

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[ { "id": "22770979__text", "type": "abstract", "text": [ "Presence of multiple independent effects in risk loci of common complex human diseases. Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the \"missing heritability\" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefore reasonable to speculate that such a phenomenon could be common among loci known to be associated with a complex trait or disease. For testing this hypothesis, a total of 117 loci known to be associated with rheumatoid arthritis (RA), Crohn disease (CD), type 1 diabetes (T1D), or type 2 diabetes (T2D) were selected. The presence of multiple independent effects was assessed in the case-control samples genotyped by the Wellcome Trust Case Control Consortium study and imputed with SNP genotype information from the HapMap Project and the 1000 Genomes Project. Eleven loci with evidence of multiple independent effects were identified in the study, and the number was expected to increase at larger sample sizes and improved statistical power. The variance explained by the multiple effects in a locus was much higher than the variance explained by the single reported SNP effect. The results thus significantly improve our understanding of the allelic structure of these individual disease-associated loci, as well as our knowledge of the general genetic mechanisms of common complex traits and diseases.\n" ], "offsets": [ [ 0, 1696 ] ] } ]

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[ { "id": "22365152__text", "type": "abstract", "text": [ "De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.\n" ], "offsets": [ [ 0, 1836 ] ] } ]

[ { "id": "22365152_T1", "type": "Gene", "text": [ "SCN8A" ], "offsets": [ [ 19, 24 ] ], "normalized": [] }, { "id": "22365152_T2", "type": "SNP", "text": [ "c.5302A>G" ], "offsets": [ [ 877, 886 ] ], "normalized": [] }, { "id": "22365152_T3", "type": "SNP", "text": [ "p.Asn1768Asp" ], "offsets": [ [ 888, 900 ] ], "normalized": [] }, { "id": "22365152_T4", "type": "Gene", "text": [ "SCN8A" ], "offsets": [ [ 944, 949 ] ], "normalized": [] }, { "id": "22365152_T5", "type": "SNP", "text": [ "p.Asn1768Asp" ], "offsets": [ [ 1395, 1407 ] ], "normalized": [] }, { "id": "22365152_T6", "type": "Gene", "text": [ "SCN8A" ], "offsets": [ [ 1641, 1646 ] ], "normalized": [] } ]

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[ { "id": "22365152_R1", "type": "AssociatedTo", "arg1_id": "22365152_T3", "arg2_id": "22365152_T4", "normalized": [] }, { "id": "22365152_R2", "type": "AssociatedTo", "arg1_id": "22365152_T2", "arg2_id": "22365152_T4", "normalized": [] } ]

[ { "id": "22405084__text", "type": "abstract", "text": [ "2011 William Allan Award: development and evolution.\n" ], "offsets": [ [ 0, 53 ] ] } ]

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[ { "id": "22703880__text", "type": "abstract", "text": [ "Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by the degeneration of lower motor neurons. The most frequent form is linked to mutations in SMN1. Childhood SMA associated with progressive myoclonic epilepsy (SMA-PME) has been reported as a rare autosomal-recessive condition unlinked to mutations in SMN1. Through linkage analysis, homozygosity mapping, and exome sequencing in three unrelated SMA-PME-affected families, we identified a homozygous missense mutation (c.125C>T [p.Thr42Met]) in exon 2 of ASAH1 in the affected children of two families and the same mutation associated with a deletion of the whole gene in the third family. Expression studies of the c.125C>T mutant cDNA in Farber fibroblasts showed that acid-ceramidase activity was only 32% of that generated by normal cDNA. This reduced activity was able to normalize the ceramide level in Farber cells, raising the question of the pathogenic mechanism underlying the CNS involvement in deficient cells. Morpholino knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord. Our results reveal a wide phenotypic spectrum associated with ASAH1 mutations. An acid-ceramidase activity below 10% results in Farber disease, an early-onset disease starting with subcutaneous lipogranulomata, joint pain, and hoarseness of the voice, whereas a higher residual activity might be responsible for SMA-PME, a later-onset phenotype restricted to the CNS and starting with lower-motor-neuron disease.\n" ], "offsets": [ [ 0, 1721 ] ] } ]

[ { "id": "22703880_T1", "type": "Gene", "text": [ "ASAH1" ], "offsets": [ [ 97, 102 ] ], "normalized": [] }, { "id": "22703880_T2", "type": "Gene", "text": [ "SMN1" ], "offsets": [ [ 295, 299 ] ], "normalized": [] }, { "id": "22703880_T3", "type": "Gene", "text": [ "SMN1" ], "offsets": [ [ 455, 459 ] ], "normalized": [] }, { "id": "22703880_T4", "type": "SNP", "text": [ "c.125C>T" ], "offsets": [ [ 622, 630 ] ], "normalized": [] }, { "id": "22703880_T5", "type": "SNP", "text": [ "p.Thr42Met" ], "offsets": [ [ 632, 642 ] ], "normalized": [] }, { "id": "22703880_T6", "type": "Gene", "text": [ "ASAH1" ], "offsets": [ [ 658, 663 ] ], "normalized": [] }, { "id": "22703880_T7", "type": "SNP", "text": [ "c.125C>T" ], "offsets": [ [ 819, 827 ] ], "normalized": [] }, { "id": "22703880_T8", "type": "Gene", "text": [ "ASAH1" ], "offsets": [ [ 1154, 1159 ] ], "normalized": [] }, { "id": "22703880_T9", "type": "Gene", "text": [ "ASAH1" ], "offsets": [ [ 1370, 1375 ] ], "normalized": [] } ]

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[ { "id": "22703880_R1", "type": "AssociatedTo", "arg1_id": "22703880_T5", "arg2_id": "22703880_T6", "normalized": [] }, { "id": "22703880_R2", "type": "AssociatedTo", "arg1_id": "22703880_T4", "arg2_id": "22703880_T6", "normalized": [] } ]

[ { "id": "22503634__text", "type": "abstract", "text": [ "Genetic adaptation of fatty-acid metabolism: a human-specific haplotype increasing the biosynthesis of long-chain omega-3 and omega-6 fatty acids. Omega-3 and omega-6 long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for the development and function of the human brain. They can be obtained directly from food, e.g., fish, or synthesized from precursor molecules found in vegetable oils. To determine the importance of genetic variability to fatty-acid biosynthesis, we studied FADS1 and FADS2, which encode rate-limiting enzymes for fatty-acid conversion. We performed genome-wide genotyping (n = 5,652 individuals) and targeted resequencing (n = 960 individuals) of the FADS region in five European population cohorts. We also analyzed available genomic data from human populations, archaic hominins, and more distant primates. Our results show that present-day humans have two common FADS haplotypes-defined by 28 closely linked SNPs across 38.9 kb-that differ dramatically in their ability to generate LC-PUFAs. No independent effects on FADS activity were seen for rare SNPs detected by targeted resequencing. The more efficient, evolutionarily derived haplotype appeared after the lineage split leading to modern humans and Neanderthals and shows evidence of positive selection. This human-specific haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and thereby might have provided an advantage in environments with limited access to dietary LC-PUFAs. In the modern world, this haplotype has been associated with lifestyle-related diseases, such as coronary artery disease.\n" ], "offsets": [ [ 0, 1643 ] ] } ]

[ { "id": "22503634_T1", "type": "Gene", "text": [ "FADS1" ], "offsets": [ [ 492, 497 ] ], "normalized": [] }, { "id": "22503634_T2", "type": "Gene", "text": [ "FADS2" ], "offsets": [ [ 502, 507 ] ], "normalized": [] } ]

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[ { "id": "22770981__text", "type": "abstract", "text": [ "HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1-/- mice. Members of the highly conserved homeobox (HOX) gene family encode transcription factors that confer cellular and tissue identities along the antero-posterior axis of mice and humans. We have identified a founder homozygous missense mutation in HOXB1 in two families from a conservative German American population. The resulting phenotype includes bilateral facial palsy, hearing loss, and strabismus and correlates extensively with the previously reported Hoxb1(-/-) mouse phenotype. The missense variant is predicted to result in the substitution of a cysteine for an arginine at amino acid residue 207 (Arg207Cys), which corresponds to the highly conserved Arg5 of the homeodomain. Arg5 interacts with thymine in the minor groove of DNA through hydrogen bonding and electrostatic attraction. Molecular modeling and an in vitro DNA-protein binding assay predict that the mutation would disrupt these interactions, destabilize the HOXB1:PBX1:DNA complex, and alter HOXB1 transcriptional activity.\n" ], "offsets": [ [ 0, 1076 ] ] } ]

[ { "id": "22770981_T1", "type": "Gene", "text": [ "HOXB1" ], "offsets": [ [ 0, 5 ] ], "normalized": [] }, { "id": "22770981_T2", "type": "Gene", "text": [ "HOXB1" ], "offsets": [ [ 323, 328 ] ], "normalized": [] }, { "id": "22770981_T3", "type": "SNP", "text": [ "Arg207Cys" ], "offsets": [ [ 684, 693 ] ], "normalized": [] }, { "id": "22770981_T6", "type": "Gene", "text": [ "HOXB1" ], "offsets": [ [ 1044, 1049 ] ], "normalized": [] } ]

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[ { "id": "22770981_R1", "type": "AssociatedTo", "arg1_id": "22770981_T3", "arg2_id": "22770981_T2", "normalized": [] } ]

[ { "id": "23122587__text", "type": "abstract", "text": [ "Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment. Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow \"U\" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.\n" ], "offsets": [ [ 0, 1879 ] ] } ]

[ { "id": "23122587_T1", "type": "Gene", "text": [ "otogelin" ], "offsets": [ [ 31, 39 ] ], "normalized": [] }, { "id": "23122587_T2", "type": "Gene", "text": [ "DFNB18" ], "offsets": [ [ 458, 464 ] ], "normalized": [] }, { "id": "23122587_T3", "type": "Gene", "text": [ "USH1C" ], "offsets": [ [ 527, 532 ] ], "normalized": [] }, { "id": "23122587_T5", "type": "Gene", "text": [ "OTOG" ], "offsets": [ [ 653, 657 ] ], "normalized": [] }, { "id": "23122587_T6", "type": "Gene", "text": [ "otogelin" ], "offsets": [ [ 677, 685 ] ], "normalized": [] }, { "id": "23122587_T7", "type": "Gene", "text": [ "murine" ], "offsets": [ [ 881, 887 ] ], "normalized": [] }, { "id": "23122587_T8", "type": "Gene", "text": [ "OTOG" ], "offsets": [ [ 973, 977 ] ], "normalized": [] }, { "id": "23122587_T9", "type": "SNP", "text": [ "c.5508delC" ], "offsets": [ [ 1035, 1045 ] ], "normalized": [] }, { "id": "23122587_T10", "type": "SNP", "text": [ "p.Ala1838ProfsX31" ], "offsets": [ [ 1119, 1136 ] ], "normalized": [] }, { "id": "23122587_T11", "type": "Gene", "text": [ "OTOG" ], "offsets": [ [ 1241, 1245 ] ], "normalized": [] }, { "id": "23122587_T12", "type": "SNP", "text": [ "c.6347C>T" ], "offsets": [ [ 1271, 1280 ] ], "normalized": [] }, { "id": "23122587_T13", "type": "SNP", "text": [ "p.Pro2116Leu" ], "offsets": [ [ 1282, 1294 ] ], "normalized": [] }, { "id": "23122587_T14", "type": "SNP", "text": [ "6559C>T" ], "offsets": [ [ 1303, 1310 ] ], "normalized": [] }, { "id": "23122587_T15", "type": "SNP", "text": [ "p.Arg2187X" ], "offsets": [ [ 1312, 1322 ] ], "normalized": [] }, { "id": "23122587_T16", "type": "SNP", "text": [ "p.Pro2116Leu" ], "offsets": [ [ 1347, 1359 ] ], "normalized": [] }, { "id": "23122587_T17", "type": "Gene", "text": [ "OTOG" ], "offsets": [ [ 1476, 1480 ] ], "normalized": [] }, { "id": "23122587_T18", "type": "Gene", "text": [ "α-tectorin" ], "offsets": [ [ 1736, 1746 ] ], "normalized": [] } ]

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[ { "id": "22405088__text", "type": "abstract", "text": [ "Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Olmsted syndrome (OS) is a rare congenital disorder characterized by palmoplantar and periorificial keratoderma, alopecia in most cases, and severe itching. The genetic basis for OS remained unidentified. Using whole-exome sequencing of case-parents trios, we have identified a de novo missense mutation in TRPV3 that produces p.Gly573Ser in an individual with OS. Nucleotide sequencing of five additional affected individuals also revealed missense mutations in TRPV3 (which produced p.Gly573Ser in three cases and p.Gly573Cys and p.Trp692Gly in one case each). Encoding a transient receptor potential vanilloid-3 cation channel, TRPV3 is primarily expressed in the skin, hair follicles, brain, and spinal cord. In transfected HEK293 cells expressing TRPV3 mutants, much larger inward currents were recorded, probably because of the constitutive opening of the mutants. These gain-of-function mutations might lead to elevated apoptosis of keratinocytes and consequent skin hyperkeratosis in the affected individuals. Our findings suggest that TRPV3 plays essential roles in skin keratinization, hair growth, and possibly itching sensation in humans and selectively targeting TRPV3 could provide therapeutic potential for keratinization or itching-related skin disorders.\n" ], "offsets": [ [ 0, 1348 ] ] } ]

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[ { "id": "22405088_R1", "type": "AssociatedTo", "arg1_id": "22405088_T3", "arg2_id": "22405088_T2", "normalized": [] }, { "id": "22405088_R2", "type": "AssociatedTo", "arg1_id": "22405088_T5", "arg2_id": "22405088_T4", "normalized": [] }, { "id": "22405088_R3", "type": "AssociatedTo", "arg1_id": "22405088_T6", "arg2_id": "22405088_T4", "normalized": [] }, { "id": "22405088_R4", "type": "AssociatedTo", "arg1_id": "22405088_T7", "arg2_id": "22405088_T4", "normalized": [] }, { "id": "22405088_R5", "type": "Equals", "arg1_id": "22405088_T8", "arg2_id": "22405088_T9", "normalized": [] } ]

[ { "id": "22243968__text", "type": "abstract", "text": [ "A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.\n" ], "offsets": [ [ 0, 1487 ] ] } ]

[ { "id": "22243968_T1", "type": "Gene", "text": [ "SMAD4" ], "offsets": [ [ 42, 47 ] ], "normalized": [] }, { "id": "22243968_T2", "type": "Gene", "text": [ "SMAD4" ], "offsets": [ [ 478, 483 ] ], "normalized": [] }, { "id": "22243968_T3", "type": "Gene", "text": [ "transducer mediating transforming growth factor β" ], "offsets": [ [ 505, 554 ] ], "normalized": [] }, { "id": "22243968_T4", "type": "Gene", "text": [ "SMAD4" ], "offsets": [ [ 664, 669 ] ], "normalized": [] }, { "id": "22243968_T5", "type": "Gene", "text": [ "SMAD4" ], "offsets": [ [ 1042, 1047 ] ], "normalized": [] } ]

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[ { "id": "22243968_R1", "type": "Equals", "arg1_id": "22243968_T3", "arg2_id": "22243968_T2", "normalized": [] } ]

[ { "id": "23122591__text", "type": "abstract", "text": [ "Response to Zhu et al.\n" ], "offsets": [ [ 0, 23 ] ] } ]

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[ { "id": "22226083__text", "type": "abstract", "text": [ "Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1. The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation.\n" ], "offsets": [ [ 0, 1918 ] ] } ]

[ { "id": "22226083_T1", "type": "Gene", "text": [ "GPD1" ], "offsets": [ [ 94, 98 ] ], "normalized": [] }, { "id": "22226083_T2", "type": "Gene", "text": [ "glycerol-3-phosphate dehydrogenase 1" ], "offsets": [ [ 109, 145 ] ], "normalized": [] }, { "id": "22226083_T3", "type": "Gene", "text": [ "GPD1" ], "offsets": [ [ 1051, 1055 ] ], "normalized": [] }, { "id": "22226083_T4", "type": "Gene", "text": [ "glycerol-3-phosphate dehydrogenase 1" ], "offsets": [ [ 1071, 1107 ] ], "normalized": [] }, { "id": "22226083_T5", "type": "SNP", "text": [ "c.361-1G>C" ], "offsets": [ [ 1168, 1178 ] ], "normalized": [] }, { "id": "22226083_T6", "type": "Gene", "text": [ "GPD1" ], "offsets": [ [ 1681, 1685 ] ], "normalized": [] }, { "id": "22226083_T7", "type": "Gene", "text": [ "GPD1" ], "offsets": [ [ 1717, 1721 ] ], "normalized": [] }, { "id": "22226083_T8", "type": "Gene", "text": [ "GPD1" ], "offsets": [ [ 1783, 1787 ] ], "normalized": [] } ]

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[ { "id": "22226083_R1", "type": "Equals", "arg1_id": "22226083_T2", "arg2_id": "22226083_T1", "normalized": [] }, { "id": "22226083_R2", "type": "Equals", "arg1_id": "22226083_T4", "arg2_id": "22226083_T3", "normalized": [] }, { "id": "22226083_R3", "type": "AssociatedTo", "arg1_id": "22226083_T5", "arg2_id": "22226083_T3", "normalized": [] } ]

[ { "id": "22387015__text", "type": "abstract", "text": [ "Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. Fibroblast growth factor receptor 2 (FGFR2) is a crucial regulator of bone formation during embryonic development. Both gain and loss-of-function studies in mice have shown that FGFR2 maintains a critical balance between the proliferation and differentiation of osteoprogenitor cells. We have identified de novo FGFR2 mutations in a sporadically occurring perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Histological analysis of the long bones revealed that the growth plate contained smaller hypertrophic chondrocytes and a thickened hypercellular periosteum. Four unrelated affected individuals were found to be heterozygous for missense mutations that introduce a polar amino acid into the hydrophobic transmembrane domain of FGFR2. Using diseased chondrocytes and a cell-based assay, we determined that these mutations selectively reduced plasma-membrane levels of FGFR2 and markedly diminished the receptor's responsiveness to extracellular FGF. All together, these clinical and molecular findings are separate from previously characterized FGFR2 disorders and represent a distinct skeletal dysplasia.\n" ], "offsets": [ [ 0, 1379 ] ] } ]

[ { "id": "22387015_T1", "type": "Gene", "text": [ "Fibroblast growth factor receptor 2" ], "offsets": [ [ 101, 136 ] ], "normalized": [] }, { "id": "22387015_T2", "type": "Gene", "text": [ "FGFR2" ], "offsets": [ [ 138, 143 ] ], "normalized": [] }, { "id": "22387015_T3", "type": "Gene", "text": [ "FGFR2" ], "offsets": [ [ 279, 284 ] ], "normalized": [] }, { "id": "22387015_T4", "type": "Gene", "text": [ "FGFR2" ], "offsets": [ [ 413, 418 ] ], "normalized": [] }, { "id": "22387015_T5", "type": "Gene", "text": [ "FGFR2." ], "offsets": [ [ 1001, 1007 ] ], "normalized": [] }, { "id": "22387015_T6", "type": "Gene", "text": [ "FGFR2" ], "offsets": [ [ 1141, 1146 ] ], "normalized": [] }, { "id": "22387015_T7", "type": "Gene", "text": [ "FGFR2" ], "offsets": [ [ 1318, 1323 ] ], "normalized": [] } ]

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[ { "id": "22387015_R1", "type": "Equals", "arg1_id": "22387015_T1", "arg2_id": "22387015_T2", "normalized": [] } ]

[ { "id": "22521416__text", "type": "abstract", "text": [ "A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by intellectual disability, reduced brain and head size, but usually without defects in cerebral cortical architecture, and other syndromic abnormalities. MCPH is heterogeneous. The underlying genes of the seven known loci code for centrosomal proteins. We studied a family from northern Pakistan with two microcephalic children using homozygosity mapping and found suggestive linkage for regions on chromosomes 2, 4, and 9. We sequenced two positional candidate genes and identified a homozygous frameshift mutation in the gene encoding the 135 kDa centrosomal protein (CEP135), located in the linkage interval on chromosome 4, in both affected children. Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. Fibroblasts obtained from one of the patients showed multiple and fragmented centrosomes, disorganized microtubules, and reduced growth rate. Similar effects were reported after knockdown of CEP135 through RNA interference; we could provoke them also by ectopic overexpression of the mutant protein. Our findings suggest an additional locus for MCPH at HSA 4q12 (MCPH8), further strengthen the role of centrosomes in the development of MCPH, and place CEP135 among the essential components of this important organelle in particular for a normal neurogenesis.\n" ], "offsets": [ [ 0, 1502 ] ] } ]

[ { "id": "22521416_T1", "type": "Gene", "text": [ "CEP135" ], "offsets": [ [ 25, 31 ] ], "normalized": [] }, { "id": "22521416_T2", "type": "Gene", "text": [ "CEP135" ], "offsets": [ [ 759, 765 ] ], "normalized": [] }, { "id": "22521416_T3", "type": "Gene", "text": [ "CEP135" ], "offsets": [ [ 1134, 1140 ] ], "normalized": [] }, { "id": "22521416_T4", "type": "Gene", "text": [ "MCPH8" ], "offsets": [ [ 1306, 1311 ] ], "normalized": [] }, { "id": "22521416_T5", "type": "Gene", "text": [ "CEP135" ], "offsets": [ [ 1395, 1401 ] ], "normalized": [] } ]

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[ { "id": "8651275__text", "type": "abstract", "text": [ "Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver. Two mutant GAMT alleles were identified that carried a single base substitution within a 5' splice site or a 13-nt insertion and gave rise to four mutant transcripts. Three of the transcripts encode truncated polypeptides that lack a residue known to be critical for catalytic activity of GAMT. Deficiency of GAMT is the first inborn error of creatine metabolism. It causes a severe developmental delay and extrapyramidal symptoms in early infancy and is treatable by oral substitution with creatine.\n" ], "offsets": [ [ 0, 808 ] ] } ]

[ { "id": "8651275_T1", "type": "Gene", "text": [ "guanidinoacetate methyltransferase" ], "offsets": [ [ 229, 263 ] ], "normalized": [] }, { "id": "8651275_T2", "type": "Gene", "text": [ "GAMT" ], "offsets": [ [ 265, 269 ] ], "normalized": [] }, { "id": "8651275_T3", "type": "Gene", "text": [ "GAMT" ], "offsets": [ [ 318, 322 ] ], "normalized": [] }, { "id": "8651275_T4", "type": "Gene", "text": [ "GAMT" ], "offsets": [ [ 596, 600 ] ], "normalized": [] }, { "id": "8651275_T5", "type": "Gene", "text": [ "GAMT" ], "offsets": [ [ 616, 620 ] ], "normalized": [] } ]

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[ { "id": "8651275_R1", "type": "Equals", "arg1_id": "8651275_T1", "arg2_id": "8651275_T2", "normalized": [] } ]

[ { "id": "8651280__text", "type": "abstract", "text": [ "Autosomal recessive Wolfram syndrome associated with an 8.5-kb mtDNA single deletion. Wolfram syndrome (MIM 222300) is characterized by optic atrophy, diabetes mellitus, diabetes insipidus, neurosensory hearing loss, urinary tract abnormalities, and neurological dysfunction. The association of clinical manifestations in tissues and organs unrelated functionally or embryologically suggested the possibility of a mitochondrial implication in the disease, which has been demonstrated in two sporadic cases. Nonetheless, familial studies suggested an autosomal recessive mode of transmission, and recent data demonstrated linkage with markers on the short arm of human chromosome 4. The patient reported here, as well as her parents and unaffected sister, carried a heteroplasmic 8.5-kb deletion in mtDNA. The deletion accounted for 23% of mitochondrial genomes in lymphocytes from the patient and approximately 5% in the tissues studied from members of her family. The presence of the deletion in the patient in a proportion higher than in her unaffected parents suggests a putative defect in a nuclear gene that acts at the mitochondrial level.\n" ], "offsets": [ [ 0, 1146 ] ] } ]

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[ { "id": "8940265__text", "type": "abstract", "text": [ "Mucopolysaccharidosis type II (Hunter syndrome): mutation \"hot spots\" in the iduronate-2-sulfatase gene. Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-chromosomal storage disorder due to deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). We have identified IDS mutations in a total of 31 families/patients with MPS II, of which 20 are novel and unique and a further 1 is novel but has been found in 3 unrelated patients. One of the mutations detected is of special interest as an AG-->G substitution in an intron, far apart from the coding region, is deleterious by creating a new 5'-splice-donor site that results in the inclusion of a 78-bp intronic sequence. While the distribution of gene rearrangements (deletions, insertions, and duplications) of <20 bp seems to be random over the IDS gene, the analysis of a total of 101 point mutations lying within the coding region shows that they tend to be more frequent in exons III, VIII, and IX. Forty-seven percent of the point mutations are at CpG dinucleotides, of which G:C-to-A:T transitions constitute nearly 80%. Almost all recurrent point mutations involve CpG sites. Analysis of a collective of 50 families studied in our laboratory, to date, revealed that mutations occur more frequently in male meioses (estimated male-to-female ratio between 3.76 and 6.3).\n" ], "offsets": [ [ 0, 1349 ] ] } ]

[ { "id": "8940265_T1", "type": "Gene", "text": [ "iduronate-2-sulfatase" ], "offsets": [ [ 77, 98 ] ], "normalized": [] }, { "id": "8940265_T2", "type": "Gene", "text": [ "iduronate-2-sulfatase" ], "offsets": [ [ 240, 261 ] ], "normalized": [] }, { "id": "8940265_T3", "type": "Gene", "text": [ "IDS" ], "offsets": [ [ 263, 266 ] ], "normalized": [] }, { "id": "8940265_T4", "type": "Gene", "text": [ "IDS" ], "offsets": [ [ 288, 291 ] ], "normalized": [] }, { "id": "8940265_T5", "type": "Gene", "text": [ "IDS" ], "offsets": [ [ 819, 822 ] ], "normalized": [] } ]

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[ { "id": "8940265_R1", "type": "Equals", "arg1_id": "8940265_T2", "arg2_id": "8940265_T3", "normalized": [] } ]

[ { "id": "8940261__text", "type": "abstract", "text": [ "The extent, mechanism, and consequences of genetic variation, for recombination rate.\n" ], "offsets": [ [ 0, 86 ] ] } ]

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[ { "id": "8651277__text", "type": "abstract", "text": [ "Maternally inherited cardiomyopathy and hearing loss associated with a novel mutation in the mitochondrial tRNA(Lys) gene (G8363A). A novel G8363A mutation in the mtDNA tRNA(Lys) gene was associated, in two unrelated families, with a syndrome consisting of encephalomyopathy, sensorineural hearing loss, and hypertrophic cardiomyopathy. Muscle biopsies from the probands showed mitochondrial proliferation and partial defects of complexes I, III, and IV of the electron-transport chain. The G8363A mutation was very abundant (>95%) in muscle samples from the probands and was less copious in blood from 18 maternal relatives (mean 81.3% +/- 8.5%). Single-muscle-fiber analysis showed significantly higher levels of mutant genomes in cytochrome (c) oxidase-negative fibers than in cytochrome (c) oxidase-positive fibers. The mutation was not found in >200 individuals, including normal controls and patients with other mitochondrial encephalomyopathies, thus fulfilling accepted criteria for pathogenicity.\n" ], "offsets": [ [ 0, 1006 ] ] } ]

[ { "id": "8651277_T1", "type": "SNP", "text": [ "G8363A" ], "offsets": [ [ 123, 129 ] ], "normalized": [] }, { "id": "8651277_T2", "type": "Gene", "text": [ "mitochondrial tRNA(Lys) gene" ], "offsets": [ [ 93, 121 ] ], "normalized": [] }, { "id": "8651277_T3", "type": "SNP", "text": [ "G8363A" ], "offsets": [ [ 140, 146 ] ], "normalized": [] }, { "id": "8651277_T4", "type": "Gene", "text": [ "mtDNA tRNA(Lys)" ], "offsets": [ [ 163, 178 ] ], "normalized": [] }, { "id": "8651277_T5", "type": "SNP", "text": [ "G8363A" ], "offsets": [ [ 491, 497 ] ], "normalized": [] } ]

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[ { "id": "8651277_R1", "type": "AssociatedTo", "arg1_id": "8651277_T1", "arg2_id": "8651277_T2", "normalized": [] }, { "id": "8651277_R2", "type": "AssociatedTo", "arg1_id": "8651277_T3", "arg2_id": "8651277_T4", "normalized": [] } ]

[ { "id": "8940267__text", "type": "abstract", "text": [ "Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. Alport syndrome is a mainly X-linked hereditary disease of basement membranes that is characterized by progressive renal failure, deafness, and ocular lesions. It is associated with mutations of the COL4A5 gene located at Xq22 and encoding the alpha5 chain of type IV collagen. We have screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and have identified 64 mutations and 10 sequence variants among 131 unrelated Alport syndrome patients. This represents a mutation-detection rate of 50%. There were no hot-spot mutations and no recurrent mutations in our population. The identified mutations were 6 nonsense mutations, 12 frameshift mutations, 17 splice-site mutations, and 29 missense mutations, 27 of the latter being glycine substitutions in the collagenous domain. Two of these occurred on the same allele in one patient and segregated with the disease in the family. We showed that some of the glycine substitutions could be associated with the lack of immunological expression of the alpha3(IV)-alpha5(IV) collagen chains in the glomerular basement membrane.\n" ], "offsets": [ [ 0, 1160 ] ] } ]

[ { "id": "8940267_T1", "type": "Gene", "text": [ "COL4A5" ], "offsets": [ [ 29, 35 ] ], "normalized": [] }, { "id": "8940267_T2", "type": "Gene", "text": [ "COL4A5" ], "offsets": [ [ 278, 284 ] ], "normalized": [] }, { "id": "8940267_T3", "type": "Gene", "text": [ "COL4A5" ], "offsets": [ [ 400, 406 ] ], "normalized": [] } ]

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[ { "id": "8651297__text", "type": "abstract", "text": [ "Mutations and phenotype in isolated glycerol kinase deficiency. We demonstrate that isolated glycerol kinase (GK) deficiency in three families results from mutation of the Xp21 GK gene. GK mutations were detected in four patients with widely differing phenotypes. Patient 1 had a splice-site mutation causing premature termination. His general health was good despite absent GK activity, indicating that isolated GK deficiency can be silent. Patient 2 had GK deficiency and a severe phenotype involving psychomotor retardation and growth delay, bone dysplasia, and seizures, similar to the severe phenotype of one of the first described cases of GK deficiency. His younger brother, patient 3, also had GK deficiency, but so far his development has been normal. GK exon 17 was deleted in both brothers, implicating additional factors in causation of the severe phenotype of patient 2. Patient 4 had both GK deficiency with mental retardation and a GK missense mutation (D440V). Possible explanations for the phenotypic variation of these four patients include ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as has previously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK deficiency on normal development.\n" ], "offsets": [ [ 0, 1356 ] ] } ]

[ { "id": "8651297_T1", "type": "Gene", "text": [ "glycerol kinase" ], "offsets": [ [ 93, 108 ] ], "normalized": [] }, { "id": "8651297_T2", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 110, 112 ] ], "normalized": [] }, { "id": "8651297_T3", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 177, 179 ] ], "normalized": [] }, { "id": "8651297_T4", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 186, 188 ] ], "normalized": [] }, { "id": "8651297_T5", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 375, 377 ] ], "normalized": [] }, { "id": "8651297_T6", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 413, 415 ] ], "normalized": [] }, { "id": "8651297_T7", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 456, 458 ] ], "normalized": [] }, { "id": "8651297_T8", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 702, 704 ] ], "normalized": [] }, { "id": "8651297_T9", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 761, 763 ] ], "normalized": [] }, { "id": "8651297_T10", "type": "SNP", "text": [ "D440V" ], "offsets": [ [ 969, 974 ] ], "normalized": [] }, { "id": "8651297_T11", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 947, 949 ] ], "normalized": [] }, { "id": "8651297_T12", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 903, 905 ] ], "normalized": [] }, { "id": "8651297_T13", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 1217, 1219 ] ], "normalized": [] }, { "id": "8651297_T14", "type": "Gene", "text": [ "GK" ], "offsets": [ [ 1319, 1321 ] ], "normalized": [] } ]

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[ { "id": "8651297_R1", "type": "Equals", "arg1_id": "8651297_T1", "arg2_id": "8651297_T2", "normalized": [] }, { "id": "8651297_R2", "type": "AssociatedTo", "arg1_id": "8651297_T10", "arg2_id": "8651297_T11", "normalized": [] } ]

[ { "id": "8755927__text", "type": "abstract", "text": [ "Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by seizures, mental retardation, and hamartomatous lesions. Although hamartomas can occur in almost any organ, they are most common in the brain, kidney, heart, and skin. Allelic loss or loss of heterozygosity (LOH) in TSC lesions has previously been reported on chromosomes 16p13 and 9q34, the locations of the TSC2 and TSC1 genes, respectively, suggesting that the TSC genes act as tumor-suppressor genes. In our study, 87 lesions from 47 TSC patients were analyzed for LOH in the TSC1 and TSC2 chromosomal regions. Three findings resulted from this analysis. First, we confirmed that the TSC1 critical region is distal to D9S149. Second, we found LOH more frequently on chromosome 16p13 than on 9q34. Of the 28 patients with angiomyolipomas or rhabdomyomas, 16p13 LOH was detected in lesions from 12 (57%) of 21 informative patients, while 9q34 LOH was detected in lesions from only 1 patient (4%). This could indicate that TSC2 tumors are more likely than TSC1 tumors to require surgical resection or that TSC2 is more common than TSC1 in our patient population. It is also possible that small regions of 9q34 LOH were missed. Lastly, LOH was found in 56% of renal angiomyolipomas and cardiac rhabdomyormas but in only 4% of TSC brain lesions. This suggests that brain lesions can result from different pathogenic mechanisms than kidney and heart lesions.\n" ], "offsets": [ [ 0, 1522 ] ] } ]

[ { "id": "8755927_T1", "type": "Gene", "text": [ "TSC2" ], "offsets": [ [ 474, 478 ] ], "normalized": [] }, { "id": "8755927_T2", "type": "Gene", "text": [ "TSC1" ], "offsets": [ [ 483, 487 ] ], "normalized": [] }, { "id": "8755927_T3", "type": "Gene", "text": [ "TSC1" ], "offsets": [ [ 645, 649 ] ], "normalized": [] }, { "id": "8755927_T4", "type": "Gene", "text": [ "TSC2" ], "offsets": [ [ 654, 658 ] ], "normalized": [] }, { "id": "8755927_T5", "type": "Gene", "text": [ "TSC1" ], "offsets": [ [ 753, 757 ] ], "normalized": [] }, { "id": "8755927_T6", "type": "Gene", "text": [ "TSC2" ], "offsets": [ [ 1089, 1093 ] ], "normalized": [] }, { "id": "8755927_T7", "type": "Gene", "text": [ "TSC1" ], "offsets": [ [ 1122, 1126 ] ], "normalized": [] }, { "id": "8755927_T8", "type": "Gene", "text": [ "TSC2" ], "offsets": [ [ 1172, 1176 ] ], "normalized": [] }, { "id": "8755927_T9", "type": "Gene", "text": [ "TSC1" ], "offsets": [ [ 1197, 1201 ] ], "normalized": [] } ]

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[ { "id": "8651311__text", "type": "abstract", "text": [ "Conclusion of LOD-score analysis for family data generated under two-locus models. The power to detect linkage by the LOD-score method is investigated here for diseases that depend on the effects of two genes. The classical strategy is, first, to detect a major-gene (MG) effect by segregation analysis and, second, to seek for linkage with genetic markers by the LOD-score method using the MG parameters. We already showed that segregation analysis can lead to evidence for a MG effect for many two-locus models, with the estimates of the MG parameters being very different from those of the two genes involved in the disease. We show here that use of these MG parameter estimates in the LOD-score analysis may lead to a failure to detect linkage for some two-locus models. For these models, use of the sib-pair method gives a non-negligible increase of power to detect linkage. The linkage-homogeneity test among subsamples differing for the familial disease distribution provides evidence of parameter misspecification, when the MG parameters are used. Moreover, for most of the models, use of the MG parameters in LOD-score analysis leads to a large bias in estimation of the recombination fraction and sometimes also to a rejection of linkage for the true recombination fraction. A final important point is that a strong evidence of an MG effect, obtained by segregation analysis, does not necessarily imply that linkage will be detected for at least one of the two genes, even with the true parameters and with a close informative marker.\n" ], "offsets": [ [ 0, 1545 ] ] } ]

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[ { "id": "8554049__text", "type": "abstract", "text": [ "Molecular definition of red cell Rh haplotypes by tightly linked SphI RFLPs. The Rh blood group system of human red cells contains five major antigens D, C/c, and E/e (the latter four designated \"non-D\") that are specified by eight gene complexes known as Rh haplotypes. In this paper, we report on the mapping of RH locus and identification of a set of SphI RFLPs that are tightly linked with the Rh structural genes. Using exon-specific probes, we have localized the SphI cleavage sites resulting in these DNA markers and derived a comprehensive map for the RH locus. It was found that the SphI fragments encompassing exons 4-7 of the Rh genes occur in four banding patterns or frameworks that correspond to the distribution and segregation of the common Rh haplotypes. This linkage disequilibrium allowed a genotype-phenotype correlation and direct determination of Rh zygosity related to the Rh-positive or Rh-negative status (D/D, D/d, and d/d). Studies on the occurrence of SphI RFLPs in a number of rare Rh variants indicated that Rh phenotypic diversity has taken place on different haplotype backgrounds and has arisen by diverse genetic mechanisms. The molecular definition of Rh haplotypes by SphI RFLP frameworks should provide a useful procedure for genetic counseling and prenatal assessment of Rh alloimmunization.\n" ], "offsets": [ [ 0, 1330 ] ] } ]

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[ { "id": "8571955__text", "type": "abstract", "text": [ "Modulation of the phenotype in dominant erythropoietic protoporphyria by a low expression of the normal ferrochelatase allele. Erythropoietic protoporphyria (EPP) is a monogenic inherited disorder of the heme biosynthetic pathway due to ferrochelatase (FC) deficiency. EPP is generally considered to be transmitted as an autosomal dominant disease with incomplete penetrance, although autosomal recessive inheritance has been documented at the enzymatic and molecular level in some families. In the dominant form of EPP, statistical analysis of FC activities documented a significantly lower mean value in patients than in asymptomatic carriers, suggesting a more complex mode of inheritance. To account for these findings, we tested a multiallelic inheritance model in one EPP family in which the enzymatic data were compatible with this hypothesis. In this EPP family, the specific FC gene mutation was an exon 10 skipping (delta Ex10), resulting from a G deletion within the exon 10 consensus splice donor site. The segregation of all FC alleles within the family was followed using the delta Ex10 mutation and a new intragenic dimorphism (1520 C/T). mRNAs transcribed from each FC allele were then subjected to relative quantification by a primer extension assay and to absolute quantification by a ribonuclease protection assay. The data support the hypothesis that in this family the EPP phenotype results from the coinheritance of a low output normal FC allele and a mutant delta Ex10 allele.\n" ], "offsets": [ [ 0, 1500 ] ] } ]

[ { "id": "8571955_T1", "type": "SNP", "text": [ "1520 C/T" ], "offsets": [ [ 1143, 1151 ] ], "normalized": [] } ]

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[ { "id": "8755923__text", "type": "abstract", "text": [ "The retrieval of ancient human DNA sequences. DNA was extracted from approximately 600-year-old human remains found at an archaeological site in the southwestern United States, and mtDNA fragments were amplified by PCR. When these fragments were sequenced directly, multiple sequences seemed to be present. From three representative individuals, DNA fragments of different lengths were quantified and short overlapping amplification products cloned. When amplifications started from <40 molecules, clones contained several different sequences. In contrast, when they were initiated by a few thousand molecules, unambiguous and reproducible results were achieved. These results show that more experimental work than is often applied is necessary to ensure that DNA sequences amplified from ancient human remains are authentic. In particular, quantitation of the numbers of amplifiable molecules is a useful tool to determine the role of contaminating contemporary molecules and PCR errors in amplifications from ancient DNA.\n" ], "offsets": [ [ 0, 1024 ] ] } ]

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[ { "id": "8755932__text", "type": "abstract", "text": [ "mtDNA sequence diversity in Africa. mtDNA sequences were determined from 241 individuals from nine ethnic groups in Africa. When they were compared with published data from other groups, it was found that the !Kung, Mbuti, and Biaka show on the order of 10 times more sequence differences between the three groups, as well as between those and the other groups (the Fulbe, Hausa, Tuareg, Songhai, Kanuri, Yoruba, Mandenka, Somali, Tukana, and Kikuyu), than these other groups do between one other. Furthermore, the pairwise sequence distributions, patterns of coalescence events, and numbers of variable positions relative to the mean sequence difference indicate that the former three groups have been of constant size over time, whereas the latter have expanded in size. We suggest that this reflects subsistence patterns in that the populations that have expanded in size are food producers whereas those that have not are hunters and gatherers.\n" ], "offsets": [ [ 0, 949 ] ] } ]

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[ { "id": "8651286__text", "type": "abstract", "text": [ "Finding genes on the X chromosome by which homo may have become sapiens.\n" ], "offsets": [ [ 0, 73 ] ] } ]

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[ { "id": "8554048__text", "type": "abstract", "text": [ "Fine mapping of the EDA gene: a translocation breakpoint is associated with a CpG island that is transcribed. In order to identify the gene for human X-linked anhidrotic ectodermal dysplasia (EDA), a translocation breakpoint in a female with t(X;1)(q13.1;p36.3) and EDA (patient AK) was finely mapped. The EDA region contains five groups of rare-cutter restriction sites that define CpG islands. The two more centromeric of these islands are associated with transcripts of 3.5 kb and 1.8 kb. The third CpG island maps within <1 kb of the translocation breakpoint in patient AK, as indicated by a genomic rearrangement, and approximately 100 kb centromeric from another previously mapped translocation breakpoint (patient AnLy). Northern analysis with a probe from this CpG island detected an approximately 6-kb mRNA in several fetal tissues tested. An extended YAC contig of 1,200 kb with an average of fivefold coverage was constructed. The two most telomeric CpG islands map 350 kb telomeric of the two translocations. Taken together, the results suggest that the CpG island just proximal of the AK translocation breakpoint lies at the 5' end of a candidate gene for EDA.\n" ], "offsets": [ [ 0, 1174 ] ] } ]

[ { "id": "8554048_T1", "type": "Gene", "text": [ "EDA" ], "offsets": [ [ 20, 23 ] ], "normalized": [] }, { "id": "8554048_T2", "type": "Gene", "text": [ "EDA" ], "offsets": [ [ 306, 309 ] ], "normalized": [] }, { "id": "8554048_T3", "type": "Gene", "text": [ "EDA" ], "offsets": [ [ 266, 269 ] ], "normalized": [] }, { "id": "8554048_T4", "type": "Gene", "text": [ "EDA" ], "offsets": [ [ 1169, 1172 ] ], "normalized": [] } ]

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[ { "id": "8751870__text", "type": "abstract", "text": [ "Family study and segregation analysis of Tourette syndrome: evidence for a mixed model of inheritance. To investigate the transmission of Tourette syndrome (TS) and associated disorders within families, complex segregation analysis was performed on family study data obtained from 53 independently ascertained children and adolescents with TS and their 154 first-degree relatives. The results suggest that the susceptibility for TS is conveyed by a major locus in combination with a multifactorial background. Other models of inheritance were definitively rejected, including strictly polygenic models, all single major locus models, and mixed models with dominant and recessive major loci. The frequency of the TS susceptibility allele was estimated to be .01. The major locus accounts for over half of the phenotypic variance for TS, whereas the multifactorial background accounts for approximately 40% of phenotypic variance. Penetrance estimates suggest that all individuals homozygous for the susceptibility allele at the major locus are affected, whereas only 2.2% of males and 0.3% of females heterozygous at the major locus are affected. Of individuals affected with TS, approximately 62% are heterozygous and approximately 38% are homozygous at the major locus. While none of the families had two parents affected with TS, 19% of families had two parents affected with the broader, phenotype, which includes TS, chronic tic disorder, or obsessive-compulsive disorder.\n" ], "offsets": [ [ 0, 1477 ] ] } ]

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[ { "id": "8940284__text", "type": "abstract", "text": [ "Using the expectation or the distribution of the identity by descent for mapping quantitative trait loci under the random model. We examine the ability of four implementations of the random model to map quantitative trait loci (QTLs). The implementations use either the expectation or the distribution of the identity-by-descent value at a putative QTL and either a 2 x 1 vector of sib-pair traits or their scalar difference. When the traits of both sibs are used, there is little difference between the expectation and distribution methods, while the expectation method suffers in both precision and power when the difference between traits is used. This is consistent with the prediction that the difference between the expectation and distribution methods is inversely proportional to the amount of information available for mapping. We find, though, that the amount of information must be very low for this difference to be noticeable. This is exemplified when both marker loci are fixed. In this case, while the expectation method is powerless to detect the QTL, the distribution method can still detect the presence (but not the position) of the QTL 59% of the time (when using trait values) or 14% of the time (when using trait differences). We also note a confounding between estimates of the QTL, polygenic, and error variance. The degree of confounding is small when the vector of trait values is used but can be substantial when the expectation method and trait differences are used. We discuss this in light of the general ability of the random model to partition these components.\n" ], "offsets": [ [ 0, 1594 ] ] } ]

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[ { "id": "8644710__text", "type": "abstract", "text": [ "The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population. Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an autosomal recessive progressive encephalopathy of childhood enriched in the western part of Finland, with a local incidence of 1 in 1500. We recently assigned the locus for vLINCL, CLN5, to 13q21.1-q32. In the present study, the haplotype analysis of Finnish CLN5 chromosomes provides evidence that one single mutation causes vLINCL in the Finnish population. Eight microsatellite markers closely linked to the CLN5 gene on chromosome 13q were analyzed, to study identity by descent by shared haplotype analysis. One single haplotype formed by flanking markers D13S160 and D13S162 in strong linkage disequilibrium (P < .0001) was present in 81% of disease-bearing chromosomes. Allele 4 at the marker locus D13S162 was detected in 94% of disease-bearing chromosomes. To evaluate the age of the CLN5 mutation by virtue of its restricted geographical distribution, church records were used to identify the common ancestors for 18 vLINCL families diagnosed in Finland. The pedigrees of the vLINCL ancestors merged on many occasions, which also supports a single founder mutation that obviously happened 20 to 30 generations ago (i.e., approximately 500 years ago) in this isolated population. Linkage disequilibrium was detected with seven markers covering an extended genetic distance of 11 cM, which further supports the young age of the CLN5 mutation. When the results of genealogical and linkage disequilibrium studies were combined, the CLN5 gene was predicted to lie approximately 200 - 400 kb (total range 30 - 1360 kb) from the closest marker D13S162.\n" ], "offsets": [ [ 0, 1749 ] ] } ]

[ { "id": "8644710_T1", "type": "Gene", "text": [ "CLN5" ], "offsets": [ [ 83, 87 ] ], "normalized": [] }, { "id": "8644710_T2", "type": "Gene", "text": [ "CLN5" ], "offsets": [ [ 374, 378 ] ], "normalized": [] }, { "id": "8644710_T3", "type": "Gene", "text": [ "CLN5" ], "offsets": [ [ 452, 456 ] ], "normalized": [] }, { "id": "8644710_T4", "type": "Gene", "text": [ "CLN5" ], "offsets": [ [ 604, 608 ] ], "normalized": [] }, { "id": "8644710_T5", "type": "Gene", "text": [ "CLN5" ], "offsets": [ [ 986, 990 ] ], "normalized": [] }, { "id": "8644710_T6", "type": "Gene", "text": [ "CLN5" ], "offsets": [ [ 1631, 1635 ] ], "normalized": [] }, { "id": "8644710_T7", "type": "Gene", "text": [ "CLN5" ], "offsets": [ [ 1529, 1533 ] ], "normalized": [] } ]

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[ { "id": "8651318__text", "type": "abstract", "text": [ "Detection of linkage to affective disorders in the catalogued Amish pedigrees: a reply to Pauls et al.\n" ], "offsets": [ [ 0, 103 ] ] } ]

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[ { "id": "8751879__text", "type": "abstract", "text": [ "The genetics of traditional living: Y-chromosomal and mitochondrial lineages in the Sinai Peninsula.\n" ], "offsets": [ [ 0, 101 ] ] } ]

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[ { "id": "18355774__text", "type": "abstract", "text": [ "SNP arrays in heterogeneous tissue: highly accurate collection of both germline and somatic genetic information from unpaired single tumor samples. SNP arrays provide reliable genotypes and can detect chromosomal aberrations at a high resolution. However, tissue heterogeneity is currently a major limitation for somatic tissue analysis. We have developed SOMATICs, an original program for accurate analysis of heterogeneous tissue samples. Fifty-four samples (42 tumors and 12 normal tissues) were processed through Illumina Beadarrays and then analyzed with SOMATICs. We demonstrate that tissue heterogeneity-related limitations not only can be overcome but can also be turned into an advantage. First, admixture of normal cells with tumor can be used as an internal reference, thereby enabling highly sensitive detection of somatic deletions without having corresponding normal tissue. Second, the presence of normal cells allows for discrimination of somatic from germline aberrations, and the proportion of cells in the tissue sample that are harboring the somatic events can be assessed. Third, relatively early versus late somatic events can also be distinguished, assuming that late events occur only in subsets of cancer cells. Finally, admixture by normal cells allows inference of germline genotypes from a cancer sample. All this information can be obtained from any cancer sample containing a proportion of 40-75% of cancer cells. SOMATICs is a ready-to-use open-source program that integrates all of these features into a simple format, comprehensively describing each chromosomal event.\n" ], "offsets": [ [ 0, 1602 ] ] } ]

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[ { "id": "19026398__text", "type": "abstract", "text": [ "Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy. We have previously reported a group of patients with congenital onset weakness associated with a deficiency of members of the syntrophin-alpha-dystrobrevin subcomplex and have demonstrated that loss of syntrophin and dystrobrevin from the sarcolemma of skeletal muscle can also be associated with denervation. Here, we have further studied four individuals from a consanguineous Egyptian family with a lethal congenital myopathy inherited in an autosomal-recessive fashion and characterized by a secondary loss of beta2-syntrophin and alpha-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. We performed homozygosity mapping and candidate gene analysis and identified a mutation that segregates with disease within CNTN1, the gene encoding for the neural immunoglobulin family adhesion molecule, contactin-1. Contactin-1 transcripts were markedly decreased on gene-expression arrays of muscle from affected family members compared to controls. We demonstrate that contactin-1 is expressed at the neuromuscular junction (NMJ) in mice and man in addition to the previously documented expression in the central and peripheral nervous system. In patients with secondary dystroglycanopathies, we show that contactin-1 is abnormally localized to the sarcolemma instead of exclusively at the NMJ. The cntn1 null mouse presents with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. We propose that loss of contactin-1 from the NMJ impairs communication or adhesion between nerve and muscle resulting in the severe myopathic phenotype. This disorder is part of the continuum in the clinical spectrum of congenital myopathies and congenital myasthenic syndromes.\n" ], "offsets": [ [ 0, 1894 ] ] } ]

[ { "id": "19026398_T1", "type": "Gene", "text": [ "contactin-1" ], "offsets": [ [ 13, 24 ] ], "normalized": [] }, { "id": "19026398_T2", "type": "Gene", "text": [ "CNTN1" ], "offsets": [ [ 895, 900 ] ], "normalized": [] }, { "id": "19026398_T3", "type": "Gene", "text": [ "contactin-1" ], "offsets": [ [ 976, 987 ] ], "normalized": [] }, { "id": "19026398_T4", "type": "Gene", "text": [ "Contactin-1" ], "offsets": [ [ 989, 1000 ] ], "normalized": [] }, { "id": "19026398_T5", "type": "Gene", "text": [ "contactin-1" ], "offsets": [ [ 1144, 1155 ] ], "normalized": [] }, { "id": "19026398_T6", "type": "Gene", "text": [ "contactin-1" ], "offsets": [ [ 1381, 1392 ] ], "normalized": [] }, { "id": "19026398_T7", "type": "Gene", "text": [ "contactin-1" ], "offsets": [ [ 1639, 1650 ] ], "normalized": [] } ]

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[ { "id": "19026398_R1", "type": "Equals", "arg1_id": "19026398_T2", "arg2_id": "19026398_T3", "normalized": [] } ]

[ { "id": "18394579__text", "type": "abstract", "text": [ "A mutation in HOXA2 is responsible for autosomal-recessive microtia in an Iranian family. Microtia, a congenital deformity manifesting as an abnormally shaped or absent external ear, occurs in one out of 8,000-10,000 births. We ascertained a consanguineous Iranian family segregating with autosomal-recessive bilateral microtia, mixed symmetrical severe to profound hearing impairment, and partial cleft palate. Genome-wide linkage analysis localized the responsible gene to chromosome 7p14.3-p15.3 with a maximum multi-point LOD score of 4.17. In this region, homeobox genes from the HOXA cluster were the most interesting candidates. Subsequent DNA sequence analysis of the HOXA1 and HOXA2 homeobox genes from the candidate region identified an interesting HOXA2 homeodomain variant: a change in a highly conserved amino acid (p.Q186K). The variant was not found in 231 Iranian and 109 Belgian control samples. The critical contribution of HoxA2 for auditory-system development has already been shown in mouse models. We built a homology model to predict the effect of this mutation on the structure and DNA-binding activity of the homeodomain by using the program Modeler 8v2. In the model of the mutant homeodomain, the position of the mutant lysine side chain is consistently farther away from a nearby phosphate group; this altered position results in the loss of a hydrogen bond and affects the DNA-binding activity.\n" ], "offsets": [ [ 0, 1424 ] ] } ]

[ { "id": "18394579_T1", "type": "Gene", "text": [ "HOXA2" ], "offsets": [ [ 14, 19 ] ], "normalized": [] }, { "id": "18394579_T2", "type": "Gene", "text": [ "HOXA1" ], "offsets": [ [ 676, 681 ] ], "normalized": [] }, { "id": "18394579_T3", "type": "Gene", "text": [ "HOXA2" ], "offsets": [ [ 686, 691 ] ], "normalized": [] }, { "id": "18394579_T4", "type": "Gene", "text": [ "HOXA2" ], "offsets": [ [ 759, 764 ] ], "normalized": [] }, { "id": "18394579_T5", "type": "Gene", "text": [ "HoxA2" ], "offsets": [ [ 942, 947 ] ], "normalized": [] }, { "id": "18394579_T6", "type": "SNP", "text": [ "p.Q186K" ], "offsets": [ [ 829, 836 ] ], "normalized": [] } ]

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[ { "id": "18394579_R1", "type": "AssociatedTo", "arg1_id": "18394579_T6", "arg2_id": "18394579_T4", "normalized": [] } ]

[ { "id": "18304497__text", "type": "abstract", "text": [ "Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. A myopathy with severe exercise intolerance and myoglobinuria has been described in patients from northern Sweden, with associated deficiencies of succinate dehydrogenase and aconitase in skeletal muscle. We identified the gene for the iron-sulfur cluster scaffold protein ISCU as a candidate within a region of shared homozygosity among patients with this disease. We found a single mutation in ISCU that likely strengthens a weak splice acceptor site, with consequent exon retention. A marked reduction of ISCU mRNA and mitochondrial ISCU protein in patient muscle was associated with a decrease in the iron regulatory protein IRP1 and intracellular iron overload in skeletal muscle, consistent with a muscle-specific alteration of iron homeostasis in this disease. ISCU interacts with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis. Our results therefore extend the range of known human diseases that are caused by defects in iron-sulfur cluster biogenesis.\n" ], "offsets": [ [ 0, 1102 ] ] } ]

[ { "id": "18304497_T1", "type": "Gene", "text": [ "iron-sulfur cluster scaffold protein" ], "offsets": [ [ 23, 59 ] ], "normalized": [] }, { "id": "18304497_T2", "type": "Gene", "text": [ "ISCU" ], "offsets": [ [ 60, 64 ] ], "normalized": [] }, { "id": "18304497_T3", "type": "Gene", "text": [ "ISCU" ], "offsets": [ [ 381, 385 ] ], "normalized": [] }, { "id": "18304497_T4", "type": "Gene", "text": [ "ISCU" ], "offsets": [ [ 504, 508 ] ], "normalized": [] }, { "id": "18304497_T5", "type": "Gene", "text": [ "ISCU" ], "offsets": [ [ 616, 620 ] ], "normalized": [] }, { "id": "18304497_T6", "type": "Gene", "text": [ "ISCU" ], "offsets": [ [ 644, 648 ] ], "normalized": [] }, { "id": "18304497_T7", "type": "Gene", "text": [ "IRP1" ], "offsets": [ [ 737, 741 ] ], "normalized": [] }, { "id": "18304497_T8", "type": "Gene", "text": [ "iron regulatory protein" ], "offsets": [ [ 713, 736 ] ], "normalized": [] }, { "id": "18304497_T9", "type": "Gene", "text": [ "ISCU" ], "offsets": [ [ 876, 880 ] ], "normalized": [] } ]

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[ { "id": "18304497_R1", "type": "Equals", "arg1_id": "18304497_T1", "arg2_id": "18304497_T2", "normalized": [] }, { "id": "18304497_R2", "type": "Equals", "arg1_id": "18304497_T8", "arg2_id": "18304497_T7", "normalized": [] } ]

[ { "id": "18460397__text", "type": "abstract", "text": [ "Differential expression of PTEN-targeting microRNAs miR-19a and miR-21 in Cowden syndrome. Germline mutations in the gene encoding phosphatase and tensin homolog deleted on chromosome ten (PTEN [MIM 601728]) are associated with a number of clinically distinct heritable cancer syndromes, including both Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). Seemingly identical pathogenic PTEN mutations have been observed in patients with CS and BRRS, as well as in patients with incomplete features of CS, referred to as CS-like (CSL) patients. These observations indicate that additional, unidentified, genetic and epigenetic factors act as phenotypic modifiers in these disorders. These genetic factors could also contribute to disease in patients with CS, CSL, or BRRS without identifiable PTEN mutations. Two potential modifiers are miR-19a and miR-21, which are previously identified PTEN-targeting miRNAs. We investigated the role of these miRNAs by characterizing their relative expression levels in PTEN-mutation-positive and PTEN-mutation-negative patients with CS, CSL, or BRRS. Interestingly, we observed differential expression of miR-19a and miR-21 in our PTEN-mutation-positive patients. Both were found to be significantly overexpressed within this group (p < 0.01) and were inversely correlated with germline PTEN protein levels. Similarly, the relative expression of miR-19a and miR-21 was differentially expressed in a series of PTEN-mutation-negative patients with CS or CSL with variable clinical phenotypes and decreased full-length PTEN protein expression. Among PTEN-mutation-positive patients with CS, both miRNAs were significantly overexpressed (p = 0.006-0.013). Taken together, our study results suggest that differential expression of PTEN-targeting miR-19a and miR-21 modulates the PTEN protein levels and the CS and CSL phenotypes, irrespective of the patient's mutation status, and support their roles as genetic modifiers in CS and CSL.\n" ], "offsets": [ [ 0, 1984 ] ] } ]

[ { "id": "18460397_T1", "type": "Gene", "text": [ "PTEN" ], "offsets": [ [ 401, 405 ] ], "normalized": [] }, { "id": "18460397_T2", "type": "Gene", "text": [ "PTEN" ], "offsets": [ [ 807, 811 ] ], "normalized": [] }, { "id": "18460397_T3", "type": "Gene", "text": [ "PTEN" ], "offsets": [ [ 1339, 1343 ] ], "normalized": [] }, { "id": "18460397_T4", "type": "Gene", "text": [ "PTEN" ], "offsets": [ [ 1568, 1572 ] ], "normalized": [] }, { "id": "18460397_T5", "type": "Gene", "text": [ "PTEN" ], "offsets": [ [ 1826, 1830 ] ], "normalized": [] }, { "id": "18460397_T6", "type": "Gene", "text": [ "PTEN" ], "offsets": [ [ 189, 193 ] ], "normalized": [] } ]

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[ { "id": "18252214__text", "type": "abstract", "text": [ "Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243A-->G mutation in blood. The mutation 3243A-->G is the most common heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutation in humans, but it is not understood why the proportion of this mutation decreases in blood during life. Changing levels of mtDNA heteroplasmy are fundamentally related to the pathophysiology of the mitochondrial disease and correlate with clinical progression. To understand this process, we simulated the segregation of mtDNA in hematopoietic stem cells and leukocyte precursors. Our observations show that the percentage of mutant mtDNA in blood decreases exponentially over time. This is consistent with the existence of a selective process acting at the stem cell level and explains why the level of mutant mtDNA in blood is almost invariably lower than in nondividing (postmitotic) tissues such as skeletal muscle. By using this approach, we derived a formula from human data to correct for the change in heteroplasmy over time. A comparison of age-corrected blood heteroplasmy levels with skeletal muscle, an embryologically distinct postmitotic tissue, provides independent confirmation of the model. These findings indicate that selection against pathogenic mtDNA mutations occurs in a stem cell population.\n" ], "offsets": [ [ 0, 1343 ] ] } ]

[ { "id": "18252214_T1", "type": "SNP", "text": [ "3243A-->G" ], "offsets": [ [ 96, 105 ] ], "normalized": [] }, { "id": "18252214_T2", "type": "SNP", "text": [ "3243A-->G" ], "offsets": [ [ 138, 147 ] ], "normalized": [] } ]

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[ { "id": "18674750__text", "type": "abstract", "text": [ "WW-domain-containing oxidoreductase is associated with low plasma HDL-C levels. Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.\n" ], "offsets": [ [ 0, 1637 ] ] } ]

[ { "id": "18674750_T1", "type": "Gene", "text": [ "WW-domain-containing oxidoreductase" ], "offsets": [ [ 351, 386 ] ], "normalized": [] }, { "id": "18674750_T2", "type": "Gene", "text": [ "WWOX" ], "offsets": [ [ 388, 392 ] ], "normalized": [] }, { "id": "18674750_T3", "type": "Gene", "text": [ "WWOX" ], "offsets": [ [ 1195, 1199 ] ], "normalized": [] }, { "id": "18674750_T4", "type": "Gene", "text": [ "WWOX" ], "offsets": [ [ 1575, 1579 ] ], "normalized": [] } ]

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[ { "id": "18674750_R1", "type": "Equals", "arg1_id": "18674750_T1", "arg2_id": "18674750_T2", "normalized": [] } ]

[ { "id": "18439549__text", "type": "abstract", "text": [ "The dawn of human matrilineal diversity. The quest to explain demographic history during the early part of human evolution has been limited because of the scarce paleoanthropological record from the Middle Stone Age. To shed light on the structure of the mitochondrial DNA (mtDNA) phylogeny at the dawn of Homo sapiens, we constructed a matrilineal tree composed of 624 complete mtDNA genomes from sub-Saharan Hg L lineages. We paid particular attention to the Khoi and San (Khoisan) people of South Africa because they are considered to be a unique relic of hunter-gatherer lifestyle and to carry paternal and maternal lineages belonging to the deepest clades known among modern humans. Both the tree phylogeny and coalescence calculations suggest that Khoisan matrilineal ancestry diverged from the rest of the human mtDNA pool 90,000-150,000 years before present (ybp) and that at least five additional, currently extant maternal lineages existed during this period in parallel. Furthermore, we estimate that a minimum of 40 other evolutionarily successful lineages flourished in sub-Saharan Africa during the period of modern human dispersal out of Africa approximately 60,000-70,000 ybp. Only much later, at the beginning of the Late Stone Age, about 40,000 ybp, did introgression of additional lineages occur into the Khoisan mtDNA pool. This process was further accelerated during the recent Bantu expansions. Our results suggest that the early settlement of humans in Africa was already matrilineally structured and involved small, separately evolving isolated populations.\n" ], "offsets": [ [ 0, 1582 ] ] } ]

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[ { "id": "18252226__text", "type": "abstract", "text": [ "Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Impaired fetal movement causes malformations, summarized as fetal akinesia deformation sequence (FADS), and is triggered by environmental and genetic factors. Acetylcholine receptor (AChR) components are suspects because mutations in the fetally expressed gamma subunit (CHRNG) of AChR were found in two FADS disorders, lethal multiple pterygium syndrome (LMPS) and Escobar syndrome. Other AChR subunits alpha1, beta1, and delta (CHRNA1, CHRNB1, CHRND) as well as receptor-associated protein of the synapse (RAPSN) previously revealed missense or compound nonsense-missense mutations in viable congenital myasthenic syndrome; lethality of homozygous null mutations was predicted but never shown. We provide the first report to our knowledge of homozygous nonsense mutations in CHRNA1 and CHRND and show that they were lethal, whereas novel recessive missense mutations in RAPSN caused a severe but not necessarily lethal phenotype. To elucidate disease-associated malformations such as frequent abortions, fetal edema, cystic hygroma, or cardiac defects, we studied Chrna1, Chrnb1, Chrnd, Chrng, and Rapsn in mouse embryos and found expression in skeletal muscles but also in early somite development. This indicates that early developmental defects might be due to somite expression in addition to solely muscle-specific effects. We conclude that complete or severe functional disruption of fetal AChR causes lethal multiple pterygium syndrome whereas milder alterations result in fetal hypokinesia with inborn contractures or a myasthenic syndrome later in life.\n" ], "offsets": [ [ 0, 1669 ] ] } ]

[ { "id": "18252226_T1", "type": "Gene", "text": [ "Acetylcholine receptor" ], "offsets": [ [ 263, 285 ] ], "normalized": [] }, { "id": "18252226_T2", "type": "Gene", "text": [ "AChR" ], "offsets": [ [ 287, 291 ] ], "normalized": [] }, { "id": "18252226_T4", "type": "Gene", "text": [ "CHRNG" ], "offsets": [ [ 375, 380 ] ], "normalized": [] }, { "id": "18252226_T3", "type": "Gene", "text": [ "AChR" ], "offsets": [ [ 385, 389 ] ], "normalized": [] }, { "id": "18252226_T5", "type": "Gene", "text": [ "AChR" ], "offsets": [ [ 494, 498 ] ], "normalized": [] }, { "id": "18252226_T6", "type": "Gene", "text": [ "CHRNA1" ], "offsets": [ [ 534, 540 ] ], "normalized": [] }, { "id": "18252226_T7", "type": "Gene", "text": [ "CHRNB1" ], "offsets": [ [ 542, 548 ] ], "normalized": [] }, { "id": "18252226_T8", "type": "Gene", "text": [ "CHRND" ], "offsets": [ [ 550, 555 ] ], "normalized": [] }, { "id": "18252226_T9", "type": "Gene", "text": [ "RAPSN" ], "offsets": [ [ 612, 617 ] ], "normalized": [] }, { "id": "18252226_T10", "type": "Gene", "text": [ "CHRNA1" ], "offsets": [ [ 881, 887 ] ], "normalized": [] }, { "id": "18252226_T11", "type": "Gene", "text": [ "CHRND" ], "offsets": [ [ 892, 897 ] ], "normalized": [] }, { "id": "18252226_T12", "type": "Gene", "text": [ "RAPSN" ], "offsets": [ [ 976, 981 ] ], "normalized": [] }, { "id": "18252226_T13", "type": "Gene", "text": [ "Chrna1" ], "offsets": [ [ 1170, 1176 ] ], "normalized": [] }, { "id": "18252226_T14", "type": "Gene", "text": [ "Chrnb1" ], "offsets": [ [ 1178, 1184 ] ], "normalized": [] }, { "id": "18252226_T15", "type": "Gene", "text": [ "Chrnd" ], "offsets": [ [ 1186, 1191 ] ], "normalized": [] }, { "id": "18252226_T16", "type": "Gene", "text": [ "Chrng" ], "offsets": [ [ 1193, 1198 ] ], "normalized": [] }, { "id": "18252226_T17", "type": "Gene", "text": [ "Rapsn" ], "offsets": [ [ 1204, 1209 ] ], "normalized": [] }, { "id": "18252226_T18", "type": "Gene", "text": [ "AChR" ], "offsets": [ [ 1502, 1506 ] ], "normalized": [] } ]

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[ { "id": "18252226_R1", "type": "Equals", "arg1_id": "18252226_T1", "arg2_id": "18252226_T2", "normalized": [] } ]

[ { "id": "18179886__text", "type": "abstract", "text": [ "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis. Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.\n" ], "offsets": [ [ 0, 1240 ] ] } ]

[ { "id": "18179886_T1", "type": "Gene", "text": [ "OSMR" ], "offsets": [ [ 423, 427 ] ], "normalized": [] }, { "id": "18179886_T2", "type": "Gene", "text": [ "oncostatin M-specific receptor beta" ], "offsets": [ [ 443, 478 ] ], "normalized": [] }, { "id": "18179886_T3", "type": "Gene", "text": [ "OSMRbeta" ], "offsets": [ [ 480, 488 ] ], "normalized": [] }, { "id": "18179886_T4", "type": "Gene", "text": [ "OSMRbeta" ], "offsets": [ [ 510, 518 ] ], "normalized": [] }, { "id": "18179886_T5", "type": "Gene", "text": [ "oncostatin M (OSM) type II receptor" ], "offsets": [ [ 541, 576 ] ], "normalized": [] }, { "id": "18179886_T6", "type": "Gene", "text": [ "interleukin (IL)-31 receptor" ], "offsets": [ [ 585, 613 ] ], "normalized": [] }, { "id": "18179886_T7", "type": "Gene", "text": [ "OSM" ], "offsets": [ [ 721, 724 ] ], "normalized": [] }, { "id": "18179886_T8", "type": "Gene", "text": [ "IL-31" ], "offsets": [ [ 728, 733 ] ], "normalized": [] }, { "id": "18179886_T9", "type": "Gene", "text": [ "OSM" ], "offsets": [ [ 933, 936 ] ], "normalized": [] }, { "id": "18179886_T10", "type": "Gene", "text": [ "IL-31" ], "offsets": [ [ 941, 946 ] ], "normalized": [] }, { "id": "18179886_T11", "type": "Gene", "text": [ "Oncostatin M receptor-beta" ], "offsets": [ [ 0, 26 ] ], "normalized": [] } ]

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[ { "id": "18179886_R1", "type": "Equals", "arg1_id": "18179886_T2", "arg2_id": "18179886_T3", "normalized": [] } ]

[ { "id": "18371931__text", "type": "abstract", "text": [ "Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Many genetic diseases have been linked to the dysfunction of primary cilia, which occur nearly ubiquitously in the body and act as solitary cellular mechanosensory organelles. The list of clinical manifestations and affected tissues in cilia-related disorders (ciliopathies) such as nephronophthisis is broad and has been attributed to the wide expression pattern of ciliary proteins. However, little is known about the molecular mechanisms leading to this dramatic diversity of phenotypes. We recently reported hypomorphic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration. Here, we chose a combinatorial approach in mice and humans to define the phenotypic spectrum of NPHP3/Nphp3 mutations and the role of the nephrocystin-3 protein. We demonstrate that the pcy mutation generates a hypomorphic Nphp3 allele that is responsible for the cystic kidney disease phenotype, whereas complete loss of Nphp3 function results in situs inversus, congenital heart defects, and embryonic lethality in mice. In humans, we show that NPHP3 mutations can cause a broad clinical spectrum of early embryonic patterning defects comprising situs inversus, polydactyly, central nervous system malformations, structural heart defects, preauricular fistulas, and a wide range of congenital anomalies of the kidney and urinary tract (CAKUT). On the functional level, we show that nephrocystin-3 directly interacts with inversin and can inhibit like inversin canonical Wnt signaling, whereas nephrocystin-3 deficiency leads in Xenopus laevis to typical planar cell polarity defects, suggesting a role in the control of canonical and noncanonical (planar cell polarity) Wnt signaling.\n" ], "offsets": [ [ 0, 1898 ] ] } ]

[ { "id": "18371931_T1", "type": "Gene", "text": [ "NPHP3" ], "offsets": [ [ 672, 677 ] ], "normalized": [] }, { "id": "18371931_T2", "type": "Gene", "text": [ "NPHP3/Nphp3" ], "offsets": [ [ 907, 918 ] ], "normalized": [] }, { "id": "18371931_T3", "type": "Gene", "text": [ "Nphp3" ], "offsets": [ [ 1034, 1039 ] ], "normalized": [] }, { "id": "18371931_T4", "type": "Gene", "text": [ "Nphp3" ], "offsets": [ [ 1133, 1138 ] ], "normalized": [] }, { "id": "18371931_T5", "type": "Gene", "text": [ "NPHP3" ], "offsets": [ [ 1258, 1263 ] ], "normalized": [] }, { "id": "18371931_T6", "type": "Gene", "text": [ "nephrocystin-3" ], "offsets": [ [ 1595, 1609 ] ], "normalized": [] }, { "id": "18371931_T7", "type": "Gene", "text": [ "nephrocystin-3" ], "offsets": [ [ 949, 963 ] ], "normalized": [] }, { "id": "18371931_T8", "type": "Gene", "text": [ "nephrocystin-3" ], "offsets": [ [ 8, 22 ] ], "normalized": [] }, { "id": "18371931_T9", "type": "Gene", "text": [ "nephrocystin-3" ], "offsets": [ [ 1706, 1720 ] ], "normalized": [] } ]

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[ { "id": "18371931_R1", "type": "Equals", "arg1_id": "18371931_T3", "arg2_id": "18371931_T7", "normalized": [] } ]

[ { "id": "19012875__text", "type": "abstract", "text": [ "Divergence between human populations estimated from linkage disequilibrium. Observed linkage disequilibrium (LD) between genetic markers in different populations descended independently from a common ancestral population can be used to estimate their absolute time of divergence, because the correlation of LD between populations will be reduced each generation by an amount that, approximately, depends only on the recombination rate between markers. Although drift leads to divergence in allele frequencies, it has less effect on divergence in LD values. We derived the relationship between LD and time of divergence and verified it with coalescent simulations. We then used HapMap Phase II data to estimate time of divergence between human populations. Summed over large numbers of pairs of loci, we find a positive correlation of LD between African and non-African populations at levels of up to approximately 0.3 cM. We estimate that the observed correlation of LD is consistent with an effective separation time of approximately 1,000 generations or approximately 25,000 years before present. The most likely explanation for such relatively low separation times is the existence of substantial levels of migration between populations after the initial separation. Theory and results from coalescent simulations confirm that low levels of migration can lead to a downward bias in the estimate of separation time.\n" ], "offsets": [ [ 0, 1418 ] ] } ]

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[ { "id": "18179903__text", "type": "abstract", "text": [ "Mutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patients. Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit (CHRNG) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1, CHRNB1, CHRND, and rapsyn (RAPSN) genes. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA, was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.\n" ], "offsets": [ [ 0, 1448 ] ] } ]

[ { "id": "18179903_T1", "type": "Gene", "text": [ "CHRNA1" ], "offsets": [ [ 21, 27 ] ], "normalized": [] }, { "id": "18179903_T2", "type": "Gene", "text": [ "CHRNB1" ], "offsets": [ [ 29, 35 ] ], "normalized": [] }, { "id": "18179903_T3", "type": "Gene", "text": [ "CHRND" ], "offsets": [ [ 37, 42 ] ], "normalized": [] }, { "id": "18179903_T4", "type": "Gene", "text": [ "RAPSN" ], "offsets": [ [ 48, 53 ] ], "normalized": [] }, { "id": "18179903_T5", "type": "Gene", "text": [ "embryonal acetylcholine receptor g" ], "offsets": [ [ 524, 558 ] ], "normalized": [] }, { "id": "18179903_T6", "type": "Gene", "text": [ "CHRNG" ], "offsets": [ [ 568, 573 ] ], "normalized": [] }, { "id": "18179903_T7", "type": "Gene", "text": [ "CHRNG" ], "offsets": [ [ 867, 872 ] ], "normalized": [] }, { "id": "18179903_T8", "type": "Gene", "text": [ "CHRNA1" ], "offsets": [ [ 904, 910 ] ], "normalized": [] }, { "id": "18179903_T9", "type": "Gene", "text": [ "CHRNB1" ], "offsets": [ [ 912, 918 ] ], "normalized": [] }, { "id": "18179903_T10", "type": "Gene", "text": [ "CHRND" ], "offsets": [ [ 920, 925 ] ], "normalized": [] }, { "id": "18179903_T11", "type": "Gene", "text": [ "rapsyn" ], "offsets": [ [ 931, 937 ] ], "normalized": [] }, { "id": "18179903_T12", "type": "Gene", "text": [ "RAPSN" ], "offsets": [ [ 939, 944 ] ], "normalized": [] }, { "id": "18179903_T13", "type": "Gene", "text": [ "CHRNA1" ], "offsets": [ [ 956, 962 ] ], "normalized": [] }, { "id": "18179903_T14", "type": "Gene", "text": [ "CHRNB1" ], "offsets": [ [ 964, 970 ] ], "normalized": [] }, { "id": "18179903_T15", "type": "Gene", "text": [ "CHRND" ], "offsets": [ [ 975, 980 ] ], "normalized": [] }, { "id": "18179903_T16", "type": "Gene", "text": [ "RAPSN" ], "offsets": [ [ 1023, 1028 ] ], "normalized": [] }, { "id": "18179903_T17", "type": "SNP", "text": [ "c.1177-1178delAA" ], "offsets": [ [ 1050, 1066 ] ], "normalized": [] }, { "id": "18179903_T18", "type": "Gene", "text": [ "RAPSN" ], "offsets": [ [ 1173, 1178 ] ], "normalized": [] } ]

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[ { "id": "18179903_R1", "type": "Equals", "arg1_id": "18179903_T11", "arg2_id": "18179903_T12", "normalized": [] }, { "id": "18179903_R2", "type": "AssociatedTo", "arg1_id": "18179903_T17", "arg2_id": "18179903_T16", "normalized": [] } ]

[ { "id": "18950739__text", "type": "abstract", "text": [ "The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. There are many thousands of hereditary diseases in humans, each of which has a specific combination of phenotypic features, but computational analysis of phenotypic data has been hampered by lack of adequate computational data structures. Therefore, we have developed a Human Phenotype Ontology (HPO) with over 8000 terms representing individual phenotypic anomalies and have annotated all clinical entries in Online Mendelian Inheritance in Man with the terms of the HPO. We show that the HPO is able to capture phenotypic similarities between diseases in a useful and highly significant fashion.\n" ], "offsets": [ [ 0, 690 ] ] } ]

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[ { "id": "18656178__text", "type": "abstract", "text": [ "A comparative analysis of the genetic epidemiology of deafness in the United States in two sets of pedigrees collected more than a century apart. In 1898, E.A. Fay published an analysis of nearly 5000 marriages among deaf individuals in America collected during the 19(th) century. Each pedigree included three-generation data on marriage partners that included at least one deaf proband, who were ascertained by complete selection. We recently proposed that the intense phenotypic assortative mating among the deaf might have greatly accelerated the normally slow response to relaxed genetic selection against deafness that began in many Western countries with the introduction of sign language and the establishment of residential schools. Simulation studies suggest that this mechanism might have doubled the frequency of the commonest forms of recessive deafness (DFNB1) in this country during the past 200 years. To test this prediction, we collected pedigree data on 311 contemporary marriages among deaf individuals that were comparable to those collected by Fay. Segregation analysis of the resulting data revealed that the estimated proportion of noncomplementary matings that can produce only deaf children has increased by a factor of more than five in the past 100 years. Additional analysis within our sample of contemporary pedigrees showed that there was a statistically significant linear increase in the prevalence of pathologic GJB2 mutations when the data on 441 probands were partitioned into three 20-year birth cohorts (1920 through 1980). These data are consistent with the increase in the frequency of DFNB1 predicted by our previous simulation studies and provide convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.\n" ], "offsets": [ [ 0, 1817 ] ] } ]

[ { "id": "18656178_T1", "type": "Gene", "text": [ "GJB2" ], "offsets": [ [ 1446, 1450 ] ], "normalized": [] } ]

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[ { "id": "18179885__text", "type": "abstract", "text": [ "Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. The T(-13910) variant located in the enhancer element of the lactase (LCT) gene correlates perfectly with lactase persistence (LP) in Eurasian populations whereas the variant is almost nonexistent among Sub-Saharan African populations, showing high prevalence of LP. Here, we report identification of two new mutations among Saudis, also known for the high prevalence of LP. We confirmed the absence of the European T(-13910) and established two new mutations found as a compound allele: T/G(-13915) within the -13910 enhancer region and a synonymous SNP in the exon 17 of the MCM6 gene T/C(-3712), -3712 bp from the LCT gene. The compound allele is driven to a high prevalence among Middle East population(s). Our functional analyses in vitro showed that both SNPs of the compound allele, located 10 kb apart, are required for the enhancer effect, most probably mediated through the binding of the hepatic nuclear factor 1 alpha (HNF1 alpha). High selection coefficient (s) approximately 0.04 for LP phenotype was found for both T(-13910) and the compound allele. The European T(-13910) and the earlier identified East African G(-13907) LP allele share the same ancestral background and most likely the same history, probably related to the same cattle domestication event. In contrast, the compound Arab allele shows a different, highly divergent ancestral haplotype, suggesting that these two major global LP alleles have arisen independently, the latter perhaps in response to camel milk consumption. These results support the convergent evolution of the LP in diverse populations, most probably reflecting different histories of adaptation to milk culture.\n" ], "offsets": [ [ 0, 1803 ] ] } ]

[ { "id": "18179885_T1", "type": "Gene", "text": [ "lactase" ], "offsets": [ [ 202, 209 ] ], "normalized": [] }, { "id": "18179885_T2", "type": "Gene", "text": [ "LCT" ], "offsets": [ [ 211, 214 ] ], "normalized": [] }, { "id": "18179885_T3", "type": "SNP", "text": [ "T/G(-13915)" ], "offsets": [ [ 629, 640 ] ], "normalized": [] }, { "id": "18179885_T4", "type": "Gene", "text": [ "MCM6" ], "offsets": [ [ 718, 722 ] ], "normalized": [] }, { "id": "18179885_T5", "type": "Gene", "text": [ "LCT" ], "offsets": [ [ 758, 761 ] ], "normalized": [] }, { "id": "18179885_T6", "type": "SNP", "text": [ "T/C(-3712)" ], "offsets": [ [ 728, 738 ] ], "normalized": [] }, { "id": "18179885_T7", "type": "Gene", "text": [ "hepatic nuclear factor 1 alpha" ], "offsets": [ [ 1040, 1070 ] ], "normalized": [] }, { "id": "18179885_T8", "type": "Gene", "text": [ "HNF1 alpha" ], "offsets": [ [ 1072, 1082 ] ], "normalized": [] } ]

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[ { "id": "18179885_R1", "type": "Equals", "arg1_id": "18179885_T1", "arg2_id": "18179885_T2", "normalized": [] }, { "id": "18179885_R2", "type": "Equals", "arg1_id": "18179885_T7", "arg2_id": "18179885_T8", "normalized": [] } ]

[ { "id": "18308288__text", "type": "abstract", "text": [ "Genome-wide high-density SNP-based linkage analysis of infantile hypertrophic pyloric stenosis identifies loci on chromosomes 11q14-q22 and Xq23. Infantile hypertrophic pyloric stenosis (IHPS) has an incidence of 1-8 per 1000 live births and is inherited as a complex sex-modified multifactorial trait with a striking male preponderance. Syndromic and monogenic forms exist, and two loci have been identified. Infants present with vomiting due to gastric-outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. A genome-wide SNP-based high-density linkage scan was carried out on 81 IHPS pedigrees. Nonparametric and parametric linkage analysis identified loci on chromosomes 11q14-q22 (Z(max) = 3.9, p < 0.0001; HLOD(max) = 3.4, alpha = 0.34) and Xq23 (Z(max) = 4.3, p < 0.00001; HLOD(max) = 4.8, alpha = 0.56). The two linked chromosomal regions each harbor functional candidate genes that are members of the canonical transient receptor potential (TRPC) family of ion channels and have a potential role in smooth-muscle control and hypertrophy.\n" ], "offsets": [ [ 0, 1070 ] ] } ]

[ { "id": "18308288_T1", "type": "Gene", "text": [ "TRPC" ], "offsets": [ [ 973, 977 ] ], "normalized": [] } ]

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[ { "id": "18423522__text", "type": "abstract", "text": [ "Estimating odds ratios in genome scans: an approximate conditional likelihood approach. In modern whole-genome scans, the use of stringent thresholds to control the genome-wide testing error distorts the estimation process, producing estimated effect sizes that may be on average far greater in magnitude than the true effect sizes. We introduce a method, based on the estimate of genetic effect and its standard error as reported by standard statistical software, to correct for this bias in case-control association studies. Our approach is widely applicable, is far easier to implement than competing approaches, and may often be applied to published studies without access to the original data. We evaluate the performance of our approach via extensive simulations for a range of genetic models, minor allele frequencies, and genetic effect sizes. Compared to the naive estimation procedure, our approach reduces the bias and the mean squared error, especially for modest effect sizes. We also develop a principled method to construct confidence intervals for the genetic effect that acknowledges the conditioning on statistical significance. Our approach is described in the specific context of odds ratios and logistic modeling but is more widely applicable. Application to recently published data sets demonstrates the relevance of our approach to modern genome scans.\n" ], "offsets": [ [ 0, 1376 ] ] } ]

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[ { "id": "18387595__text", "type": "abstract", "text": [ "On the replication of genetic associations: timing can be everything! The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing \"age-varying associations.\" If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.\n" ], "offsets": [ [ 0, 1510 ] ] } ]

[ { "id": "18387595_T1", "type": "Gene", "text": [ "ROBO1" ], "offsets": [ [ 789, 794 ] ], "normalized": [] } ]

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[ { "id": "18452888__text", "type": "abstract", "text": [ "Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome. Brittle cornea syndrome (BCS) is an autosomal-recessive disorder characterized by a thin cornea that tends to perforate, causing progressive visual loss and blindness. Additional systemic symptoms such as joint hypermotility, hyperlaxity of the skin, and kyphoscoliosis place BCS among the connective-tissue disorders. Previously, we assigned the disease gene to a 4.7 Mb interval on chromosome 16q24. In order to clone the BCS gene, we first narrowed the disease locus to a 2.8 Mb interval and systematically sequenced genes expressed in connective tissue in this chromosomal segment. We have identified two frameshift mutations in the Zinc-Finger 469 gene (ZNF469). In five unrelated patients of Tunisian Jewish ancestry, we found a 1 bp deletion at position 5943 (5943 delA), and in an inbred Palestinian family we detected a single-nucleotide deletion at position 9527 (9527 delG). The function of ZNF469 is unknown. However, a 30% homology to a number of collagens suggests that it could act as a transcription factor involved in the synthesis and/or organization of collagen fibers.\n" ], "offsets": [ [ 0, 1170 ] ] } ]

[ { "id": "18452888_T1", "type": "Gene", "text": [ "Zinc-Finger 469" ], "offsets": [ [ 29, 44 ] ], "normalized": [] }, { "id": "18452888_T3", "type": "Gene", "text": [ "Zinc-Finger 469" ], "offsets": [ [ 718, 733 ] ], "normalized": [] }, { "id": "18452888_T4", "type": "Gene", "text": [ "ZNF469" ], "offsets": [ [ 740, 746 ] ], "normalized": [] }, { "id": "18452888_T5", "type": "SNP", "text": [ "5943 delA" ], "offsets": [ [ 848, 857 ] ], "normalized": [] }, { "id": "18452888_T6", "type": "SNP", "text": [ "9527 delG" ], "offsets": [ [ 955, 964 ] ], "normalized": [] }, { "id": "18452888_T7", "type": "Gene", "text": [ "ZNF469" ], "offsets": [ [ 983, 989 ] ], "normalized": [] } ]

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