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The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

ABSTRACT: Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.

SUBMITTER: Zazo Seco C

PROVIDER: S-EPMC5315517 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

Zazo Seco Celia C Wesdorp Mieke M Feenstra Ilse I Pfundt Rolph R Hehir-Kwa Jayne Y JY Lelieveld Stefan H SH Castelein Steven S Gilissen Christian C de Wijs Ilse J IJ Admiraal Ronald Jc RJ Pennings Ronald Je RJ Kunst Henricus Pm HP van de Kamp Jiddeke M JM Tamminga Saskia S Houweling Arjan C AC Plomp Astrid S AS Maas Saskia M SM de Koning Gans Pia Am PA Kant Sarina G SG de Geus Christa M CM Frints Suzanna Gm SG Vanhoutte Els K EK van Dooren Marieke F MF van den Boogaard Marie-José H MH Scheffer Hans H Nelen Marcel M Kremer Hannie H Hoefsloot Lies L Schraders Margit M Yntema Helger G HG

European journal of human genetics : EJHG 20161221 3

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying ...[more]

PMID: 28000701

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Project description:Importance:Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown. Objective:To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors. Design:Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children's hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record. Main Outcomes and Measures:Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations. Results:Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%). Conclusions and Relevance:Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.

Dataset Information

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

Publications

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.

Similar Datasets

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