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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.

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


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.


hereditary hearing loss; mutation classification system; targeted resequencing

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