Abstract
BackgroundMYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which ultimately requires cochlear implantation in early childhood. Recently, such variants have also been shown to possibly cause moderate-to-severe hearing loss. Herein, we also demonstrate that some MYO15A mutant alleles can cause postlingual onset of progressive partial deafness.MethodsTwo multiplex Korean families (SB246 and SB224), manifesting postlingual, progressive, partial deafness in an autosomal recessive fashion, were recruited. Molecular genetics testing was performed in two different pipelines, in a parallel fashion, for the SB246 family: targeted exome sequencing (TES) of 129 known deafness genes from the proband and whole exome sequencing (WES) of all affected subjects. Only the former pipeline was performed for the SB224 family. Rigorous bioinformatics analyses encompassing structural variations were executed to investigate any causative variants.ResultsIn the SB246 family, two different molecular diagnostic pipelines provided exactly the same candidate variants: c.5504G > A (p.R1835H) in the motor domain and c.10245_10247delCTC (p.S3417del) in the FERM domain of MYO15A. In the SB224 family, c.9790C > T (p.Q3264X) and c.10263C > G (p.I3421M) in the FERM domain were detected as candidate variants.ConclusionsSome recessive MYO15A variants can cause postlingual onset of progressive partial deafness. The phenotypic spectrum of DFNB3 should be extended to include such partial deafness. The mechanism for a milder phenotype could be due to the milder pathogenic potential from hypomorphic alleles of MYO15A or the presence of modifier genes. This merits further investigation.
Highlights
MYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which requires cochlear implantation in early childhood
It was later discovered that the phenotypes of MYO15A pathogenic variants varied depending on the affected domain
We suggest that MYO15A may be a causative gene responsible for the postlingual onset of progressive partial deafness, which in turn requires the expansion of the phenotypic spectrum of MYO15A pathogenic variants
Summary
MYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which requires cochlear implantation in early childhood. Such variants have been shown to possibly cause moderate-to-severe hearing loss. The role of myosin XVA, which is encoded by MYO15A, includes the graded elongation and maintenance of stereocilia and actin-organization in the inner ear hair cells. These are both essential for normal auditory function. MYO15A pathogenic variants that reside in the regions shared by both isoforms are known to cause congenital or prelingual severe-toprofound hearing loss [7]
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