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Hum Mutat. 2016 Aug;37(8):812-9. doi: 10.1002/humu.22999. Epub 2016 May 6.

DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System.

Author information

1
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
2
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
3
Antwerp University Hospital, Antwerp, Belgium.
4
Department of Otorhinolaryngology, Head & Neck Surgery, Antwerp University Hospital, Antwerp, Belgium.
5
Center of Medical Genetics, Ghent University, Ghent, Belgium.
6
University Department Otolaryngology, St. Augustinus Hospital, Antwerp, Belgium.
7
Inner Ear Lab, Department of Otolaryngology, University Medical Center Göttingen, Göttingen, Germany.
8
Clinical and Molecular Genetics Unit, UCL Institute of Child Health and Great Ormond Street Hospital NHS Trust, London, UK.
9
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.

Abstract

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.

KEYWORDS:

hereditary hearing loss; mutation classification system; targeted resequencing

PMID:
27068579
DOI:
10.1002/humu.22999
[Indexed for MEDLINE]

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