Identification of novel MYH14 variants in families with autosomal dominant sensorineural hearing loss

Abstract

Autosomal dominant sensorineural hearing loss (ADSNHL) is a genetically heterogeneous disorder caused by pathogenic variants in various genes, including MYH14. However, the interpretation of pathogenicity for MYH14 variants remains a challenge due to incomplete penetrance and the lack of functional studies and large families. In this study, we performed exome sequencing in six unrelated families with ADSNHL and identified five MYH14 variants, including three novel variants. Two of the novel variants, c.571G > C (p.Asp191His) and c.571G > A (p.Asp191Asn), were classified as likely pathogenic using ACMG and Hearing Loss Expert panel guidelines. In silico modeling demonstrated that these variants, along with p.Gly1794Arg, can alter protein stability and interactions among neighboring molecules. Our findings suggest that MYH14 causative variants may be more contributory and emphasize the importance of considering this gene in patients with nonsyndromic mainly post-lingual severe form of hearing loss. However, further functional studies are needed to confirm the pathogenicity of these variants.

Keywords: MYH14; gene; hearing loss; pathogenic variant.

Figure 1.

Pedigrees, audiograms and chromatograms of identified novel likely pathogenic variants in MYH14. (A) Pedigrees of families. (B) The protein alignment shows conservation across 24 vertebrates including five diverse classes for the 191Asp residue by using Multiz Alignments at https://genome.ucsc.edu/. (C) Chromatograms showing the identified variants.

Figure 2.

Structural modelling of novel pathogenic variants in MYH14. A) The substitution of Asp to Asn at position 191 disrupts the interaction with neighboring amino acid. B) Asp at position 191 is replaced with Histidine; a basic polar amino acid which has interrupted the interactions with adjacent amino acid in the chain. C) Glycine is a small amino acid which is replaced by Arginine at position 1794. Arginine being a large hydrophilic amino acid has developed additional bonding with the amino acids in the vicinity which may cause additional constraint on the structure. Mutated amino acid residues are indicated in green. Red dotted lines show hydrogen bonding, grey dotted lines represent aromatic contacts and yellow dotted lines represent ionic interactions.