Exome Sequencing Identifies a Novel Frameshift Mutation ofMYO6as the Cause of Autosomal Dominant Nonsyndromic Hearing Loss in a Chinese Family

Abstract

SummaryAutosomal dominant types of nonsyndromic hearing loss (ADNSHL) are typically postlingual in onset and progressive. High genetic heterogeneity, late onset age, and possible confounding due to nongenetic factors hinder the timely molecular diagnoses for most patients. In this study, exome sequencing was applied to investigate a large Chinese family segregating ADNSHL in which we initially failed to find strong evidence of linkage to any locus by whole-genome linkage analysis. Two affected family members were selected for sequencing. We identified two novel mutations disrupting known ADNSHL genes and shared by the sequenced samples: c.328C>A in COCH (DFNA9) resulting in a p.Q110K substitution and a deletion c. 2814_2815delAA in MYO6 (DFNA22) causing a frameshift alteration p.R939Tfs * 2. The pathogenicity of novel coding variants in ADNSHL genes was carefully evaluated by analysis of co-segregation with phenotype in the pedigree and in light of established genotype-phenotype correlations. The frameshift deletion in MYO6 was confirmed as the causative variant for this pedigree, whereas the missense mutation in COCH had no clinical significance. The results allowed us to retrospectively identify the phenocopy in one patient that contributed to the negative finding in the linkage scan. Our clinical data also supported the emerging genotype-phenotype correlation for DFNA22.

A clinical guidance to DFNA22 drawn from a Korean cohort study with an autosomal dominant deaf population: A retrospective cohort study

“…As described earlier in the Results, various audiogram configurations existed among the Korean DFNA22 patients. Interestingly, SB60–107 (M/14) in the present study (Figure B) and two affected members (F/35 and M/38) from the Chinese study demonstrated strikingly asymmetric HL, which was not observed in the Caucasian populations. This might be a phenomenon specifically found in East Asian DFNA22 cohorts.…”

“…[8][9][10][11][12][13][14][15][16][17][18] Hereditary deafness related to MYO6 captures the interest of both clinicians and researchers because it can be either an autosomal dominant (AD)-or autosomal recessive (AR)-inherited disease, representing a wide spectrum of clinical phenotypes in accordance with the studies mentioned above. 5,6,[8][9][10][11][12][13][14][15][16][17][18] Moreover, MYO6 was found to significantly contribute to AD-inherited genetic hearing loss (HL) in the Korean deaf populations, with five novel variants being reported. 8,12 Although MYO6 is a well-known and widespread deafness gene reported in more than 10 countries, its diverse clinical features make it difficult to produce a set guideline for counselling patients (as well as their family) with MYO6 variants.…”

“…Hereditary deafness related to MYO6 captures the interest of both clinicians and researchers because it can be either an autosomal dominant (AD)‐ or autosomal recessive (AR)‐inherited disease, representing a wide spectrum of clinical phenotypes in accordance with the studies mentioned above . Moreover, MYO6 was found to significantly contribute to AD‐inherited genetic hearing loss (HL) in the Korean deaf populations, with five novel variants being reported .…”

“…By contrast, audiological phenotypes of DFNB37 caused by recessive MYO6 mutant alleles from three different causative alleles were rather consistent with respect to congenital onset and a degree of at least severe HL . Clarification of genotype–phenotype correlations underlying diverse phenotypes of DFNA22, if any, were pursued; however, variants were distributed along the whole domains of myosin VI and interfamilial or even intrafamilial variation existent under the same variant made it almost impossible to characterize the genotype–phenotype correlation in DFNA22 . Surprisingly, even the same variant, p.R1166X, of MYO6 showed different phenotypes of DFNA22 (mild degree of HL starting in their thirties) and DFNB37 (congenital profound HL) in the Japanese and Pakistani population, respectively .…”

“…the mouse homologue of MYO6 ) is altered, this can cause Snell's Waltzer in mice, which manifests as deafness and vestibular dysfunction . Subsequent to the identification of MYO6 as a deafness gene, 17 variants of DFNA22 and five variants of DFNB37 have been reported …”