Dataset Information

Challenges in whole exome sequencing: an example from hereditary deafness.

ABSTRACT: Whole exome sequencing provides unprecedented opportunities to identify causative DNA variants in rare Mendelian disorders. Finding the responsible mutation via traditional methods in families with hearing loss is difficult due to a high degree of genetic heterogeneity. In this study we combined autozygosity mapping and whole exome sequencing in a family with 3 affected children having nonsyndromic hearing loss born to consanguineous parents. Two novel missense homozygous variants, c.508C>A (p.H170N) in GIPC3 and c.1328C>T (p.T443M) in ZNF57, were identified in the same ?6 Mb autozygous region on chromosome 19 in affected members of the family. Both variants co-segregated with the phenotype and were absent in 335 ethnicity-matched controls. Biallelic GIPC3 mutations have recently been reported to cause autosomal recessive nonsyndromic sensorineural hearing loss. Thus we conclude that the hearing loss in the family described in this report is caused by a novel missense mutation in GIPC3. Identified variant in GIPC3 had a low read depth, which was initially filtered out during the analysis leaving ZNF57 as the only potential causative gene. This study highlights some of the challenges in the analyses of whole exome data in the bid to establish the true causative variant in Mendelian disease.

SUBMITTER: Sirmaci A

PROVIDER: S-EPMC3283682 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Challenges in whole exome sequencing: an example from hereditary deafness.

Sirmaci Asli A Edwards Yvonne J K YJ Akay Hatice H Tekin Mustafa M

PloS one 20120221 2

Whole exome sequencing provides unprecedented opportunities to identify causative DNA variants in rare Mendelian disorders. Finding the responsible mutation via traditional methods in families with hearing loss is difficult due to a high degree of genetic heterogeneity. In this study we combined autozygosity mapping and whole exome sequencing in a family with 3 affected children having nonsyndromic hearing loss born to consanguineous parents. Two novel missense homozygous variants, c.508C>A (p.H ...[more]

PMID: 22363784

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Project description:ImportanceThe E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown.ObjectiveTo assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC.Design, setting, and participantsThis cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020.Main outcomes and measuresIncidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC.ResultsAmong 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC.Conclusions and relevanceThis study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

Project description:Background:Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods:Using 11?990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided. Results:Strong signals were detected for CDKN2A (Pmin = 6.16?×?10-8) in the CM cohort (n?=?273) and BAP1 (Pmin = 3.83?×?10-6) in the OM (n?=?99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379?CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75?×?10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37?×?10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions:The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.

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Dataset Information

Challenges in whole exome sequencing: an example from hereditary deafness.

Publications

Challenges in whole exome sequencing: an example from hereditary deafness.

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