Title
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DNA diagnostics of hereditary hearing loss : a targeted resequencing approach combined with a mutation classification system
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Author
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Abstract
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Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing-based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, there is a need for high-throughput diagnostic methods to detect disease-causing variations, including single-nucleotide variations (SNVs), insertions/deletions (Indels), and copy-number variations (CNVs). In this study, a targeted resequencing panel for hearing loss was developed including 79 genes for NSHL and selected forms of syndromic hearing loss. One-hundred thirty one presumed autosomal-recessive NSHL (arNSHL) patients of Western-European ethnicity were analyzed for SNVs, Indels, and CNVs. In addition, we established a straightforward variant classification system to deal with the large number of variants encountered. We estimate that combining prescreening of GJB2 with our panel leads to a diagnosis in 25%-30% of patients. Our data show that after GJB2, the most commonly mutated genes in a Western-European population are TMC1, MYO15A, and MYO7A (3.1%). CNV analysis resulted in the identification of causative variants in two patients in OTOA and STRC. One of the major challenges for diagnostic gene panels is assigning pathogenicity for variants. A collaborative database collecting all identified variants from multiple centers could be a valuable resource for hearing loss diagnostics. |
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Language
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English
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Source (journal)
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Human mutation. - New York, N.Y.
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Publication
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New York, N.Y.
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2016
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ISSN
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1059-7794
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DOI
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10.1002/HUMU.22999
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Volume/pages
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37
:8
(2016)
, p. 812-819
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ISI
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000379932300012
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Pubmed ID
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27068579
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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