Novel SLITRK6 Nonsense Mutation in an Iranian Family with Autosomal Recessive Syndromic Hearing Loss

Abstract

SLITRK6 is essential for inner-ear neuronal survival and retinal development, and pathogenic variants in this gene cause syndromic sensorineural hearing loss (HL) with high myopia. This study aimed to identify the genetic basis of HL and myopia in a consanguineous Iranian family with two affected children and to characterize the molecular consequences of the detected variant. One sibling with bilateral congenital HL and myopia was evaluated using whole-exome sequencing (WES). Common variants (MAF >1%) were excluded, and rare exonic changes were prioritized. Variant pathogenicity was assessed according to ACMG guidelines, and segregation was confirmed by Sanger sequencing in two affected children and their parents. ProtParam was used to compare physicochemical properties of wild-type and truncated proteins, and STRING was applied to assess predicted protein-protein interactions. WES identified a novel homozygous nonsense variant in SLITRK6, NM_032229.3:c.1795C>T (p.Arg599Ter), located in exon 2. The parents were heterozygous carriers, and the variant was ultra-rare in public databases. In silico analyses predicted that the premature termination codon produces a truncated protein with loss-of-function effects. These findings are consistent with previously described SLITRK6-associated HL with myopia. We report a novel likely pathogenic SLITRK6 variant associated with congenital HL and myopia in an Iranian family. The predicted loss-of-function supports an important role for SLITRK6 in auditory and visual system development. Further studies are needed to elucidate the molecular mechanisms underlying SLITRK6-related disorders.