Targeted and Genomewide NGS Data Disqualify Mutations in MYO1A, the "DFNA48 Gene", as a Cause of Deafness. Issue 5 (31st March 2014)

• Record Type: Journal Article
• Authors: Eisenberger, Tobias; Di Donato, Nataliya; Baig, Shahid M.; Neuhaus, Christine; Beyer, Anke; Decker, Eva; Mürbe, Dirk; Decker, Christian; Bergmann, Carsten; Bolz, Hanno J.
• Is Part Of: Human mutation. Volume 35:Issue 5(2014:May)
• Page Start: 565
• Page End: 570
• Publication Date: 2014-03-31
• Subjects: Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.22532
• Languages: English
• ISSNs: 1059-7794

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p> <italic>MYO1A</italic> is considered the gene underlying autosomal dominant nonsyndromic hearing loss <italic>DFNA48</italic>, based on six missense variants, one small <italic>in‐frame</italic> insertion, and one nonsense mutation. Results from NGS targeting 66 deafness genes in 109 patients identified three families challenging this assumption: two novel nonsense (p.Tyr740* and p.Arg262*) and a known missense variant were identified heterozygously not only in index patients, but also in unaffected relatives. Deafness in these families clearly resulted from mutations in other genes (<italic>MYO7A</italic>, <italic>EYA1</italic>, and <italic>CIB2</italic>). Most of the altogether 10 <italic>MYO1A</italic> mutations are annotated in dbSNP, and population frequencies (dbSNP, 1000 Genomes, Exome Sequencing Project) above 0.1% contradict pathogenicity under a dominant model. One healthy individual was even homozygous for p.Arg262*, compatible with homozygous <italic>Myo1a</italic> knockout mice lacking any overt pathology. <italic>MYO1A</italic> seems dispensable for hearing and overall nonessential. <italic>MYO1A</italic> adds to the list of "erroneous disease genes", which will expand with increasing availability of large‐scale sequencing data.</p> </abstract>