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Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing.

Authors
  • Brownstein, Zippora
  • Abu-Rayyan, Amal
  • Karfunkel-Doron, Daphne
  • Sirigu, Serena
  • Davidov, Bella
  • Shohat, Mordechai
  • Frydman, Moshe
  • Houdusse, Anne
  • Kanaan, Moien
  • Avraham, Karen B
Type
Published Article
Journal
European Journal of Human Genetics
Publisher
Springer Nature
Publication Date
Jun 01, 2014
Volume
22
Issue
6
Pages
768–775
Identifiers
DOI: 10.1038/ejhg.2013.232
PMID: 24105371
Source
Medline
License
Unknown

Abstract

Hereditary hearing loss is genetically heterogeneous, with a large number of genes and mutations contributing to this sensory, often monogenic, disease. This number, as well as large size, precludes comprehensive genetic diagnosis of all known deafness genes. A combination of targeted genomic capture and massively parallel sequencing (MPS), also referred to as next-generation sequencing, was applied to determine the deafness-causing genes in hearing-impaired individuals from Israeli Jewish and Palestinian Arab families. Among the mutations detected, we identified nine novel mutations in the genes encoding myosin VI, myosin VIIA and myosin XVA, doubling the number of myosin mutations in the Middle East. Myosin VI mutations were identified in this population for the first time. Modeling of the mutations provided predicted mechanisms for the damage they inflict in the molecular motors, leading to impaired function and thus deafness. The myosin mutations span all regions of these molecular motors, leading to a wide range of hearing phenotypes, reinforcing the key role of this family of proteins in auditory function. This study demonstrates that multiple mutations responsible for hearing loss can be identified in a relatively straightforward manner by targeted-gene MPS technology and concludes that this is the optimal genetic diagnostic approach for identification of mutations responsible for hearing loss.

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