Three mutations, c.3971C>A (p.A1324D), c.4011insA (p.Q1337Qfs*22), and c.9690 + 1G>A, were detected in MYO15A gene (NM_016239), which were cosegregated with the disease, suggesting that these mutations may be the etiology of deafness in this ARNSHL family.
DFNB3 is the third pathogenic locus responsible for severe to profound ARNSHL. This report performed targeted capture sequence of 127 known deafness genes to describe genetic causes of a Chinese ARNSHL family.
The present results also demonstrated that the combined application of SNPscan assay and targeted capture sequencing is a valuable and cost-saving molecular diagnostic strategy for ARNSHL. Our findings further extended the pathogenic variants of MYO15A gene in the ARNSHL group and would have a positive implication in genetic counseling for hearing loss families.
Although several causative mutations in TMPRSS3 have been identified, little is known about the contribution of this gene to ARNSHL in the Chinese population.
The 150 affected patients originated from 150 families presenting with ARNSHL, in whom previous screening had found no mutations within the GJB2 or SLC26A4 genes.
All of the 13 exons and 100 bp of exon-intron boundaries of TMPRSS3 (NM_024022.2) were screened via Sanger sequencing of DNA from 150 index patients of ARNSHL families.
In our previous study of one Chinese ARNSHL family (FH1523), three disease-segregating mutations in TMPRSS3 (c.916G>A, p.Ala306Thr; c.316C>T, p.Arg106Cys; and c.36delC, p.Pro12fs) were identified and described .
Table 2 summarizes clinical characteristics of 14 patients from seven ARNSHL families with TMPRSS3 mutations including onset age, audiogram configuration, progression of hearing loss, and vestibular symptoms.
The typical ski-slope audiogram configuration in ARNSHL is suggestive of TMPRSS3 involvement, with a hearing phenotype and inheritance similar to those of SLC26A4.
Table 3 summarizes the type, position, origin, and mutation classification of the 39 TMPRSS3 mutations reported to date, which are associated with ARNSHL in more than 15 ethnic groups worldwide.