Expanding the genetic landscape of MYO15A: Discovery of a novel splice-region variant in an Iranian family and insights into splicing variants.

BACKGROUND

Variants in MYO15A are an important cause of autosomal recessive non-syndromic sensorineural hearing loss (DFNB3). Non-canonical splicing variants remain challenging to interpret without transcript-level evidence.

METHODS

We investigated a consanguineous Iranian family affected by congenital profound non-syndromic hearing loss. Exome sequencing, segregation analysis, and in silico splice prediction tools were applied. A structured literature review of reported MYO15A splicing variants was also performed.

RESULTS

A novel homozygous MYO15A non-canonical splice-region variant, c.9230-3C>T (intron 54), was identified in the affected individual. The variant co-segregated with the disease within the family. Splice-prediction algorithms consistently indicated weakening the splice acceptor site, suggesting a potential splice-altering effect. Based on ACMG criteria, the variant was classified as of likely pathogenic. A structured literature review of splicing variants across multiple families revealed a predominance of severe-to-profound hearing loss among affected individuals, underscoring the clinical relevance of splicing disruption in MYO15A.

CONCLUSIONS

This study broadens the understanding of the genetic diversity of MYO15A by identifying a novel non-canonical splice-region variant in an Iranian family. Additionally, we present an updated review of known MYO15A splicing variants. Functional RNA-based assays are required to determine the molecular consequence of this non-canonical splice-region variant and to enable definitive clinical classification.