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Targeted and Genomewide NGS Data Disqualify Mutations in MYO 1 A , the “ DFNA 48 Gene”, as a Cause of Deafness
Author(s) -
Eisenberger Tobias,
Di Donato Nataliya,
Baig Shahid M.,
Neuhaus Christine,
Beyer Anke,
Decker Eva,
Mürbe Dirk,
Decker Christian,
Bergmann Carsten,
Bolz Hanno J.
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22532
Subject(s) - dbsnp , biology , genetics , missense mutation , 1000 genomes project , exome sequencing , nonsense mutation , exome , nonsense , gene , population , mutation , single nucleotide polymorphism , genotype , medicine , environmental health
MYO1A is considered the gene underlying autosomal dominant nonsyndromic hearing loss DFNA 48 , based on six missense variants, one small in‐frame 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 ( MYO 7 A , EYA 1 , and CIB 2 ). Most of the altogether 10 MYO 1 A mutations are annotated in db SNP , and population frequencies (db SNP , 1000 G enomes, E xome S equencing P roject) above 0.1% contradict pathogenicity under a dominant model. One healthy individual was even homozygous for p.Arg262*, compatible with homozygous Myo1a knockout mice lacking any overt pathology. MYO 1 A seems dispensable for hearing and overall nonessential. MYO 1 A adds to the list of “erroneous disease genes”, which will expand with increasing availability of large‐scale sequencing data.