Targeted and Genomewide NGS Data Disqualify Mutations inMYO1A, the “DFNA48Gene”, as a Cause of Deafness

Abstract

MYO1A is considered the gene underlying autosomal dominant nonsyndromic hearing loss DFNA48, 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 (MYO7A, EYA1, and CIB2). Most of the altogether 10 MYO1A 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 Myo1a knockout mice lacking any overt pathology. MYO1A seems dispensable for hearing and overall nonessential. MYO1A adds to the list of "erroneous disease genes", which will expand with increasing availability of large-scale sequencing data.

Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss

“…Since our sequencing program was started before 2014 when MYO1A was still considered to be an autosomal dominant nonsyndromic hearing loss gene on the Hereditary Hearing Loss website (www.hereditaryhearingloss.org), so MYO1A was included in the 60 sequencing genes in our study. However, an NGS study targeting 66 genes in 109 patients conducted by Eisenberger et al in 2014 indicated the nonpathogenicity of three MYO1A variants and challenged the previous understanding of MYO1A (Eisenberger et al, 2014). At almost the same time, a separate study reached the same conclusion (Kim et al, 2015).…”

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource

“…Some of the gene-disease relationships are either unable to be confirmed for many years or are ultimately proven wrong. 4 Evaluating the clinical impact of variants identified in genes with an unclear role in disease is exceedingly difficult and could lead to incorrect diagnoses, preventing further evaluations and/or resulting in errant management of the affected individual and their families. This scenario highlights the need for a standardized method to evaluate the evidence implicating a gene in disease and thereby determine the clinical validity 2 of a gene-disease relationship.…”

A genotypic ascertainment approach to refute the association of MYO1A variants with non-syndromic deafness

“…4 In another study, deafness-associated genes were evaluated in a cohort of 109 hearing-impaired individuals. 3 In summary, we have employed a genotype ascertainment study design that refutes the conclusion that mutations in MYO1A cause ADNSHL. When combined with published mouse data and other human data that fail to support this hypothesis, there are now more studies arguing against pathogenicity, as opposed to the single initial study in favor of pathogenicity.…”

“…However, it is unclear whether this is valid. 3,4 We set out to test this hypothesis using a distinct approach.…”