The predicted loss-of-function of SLITRK6 supports an important role for SLITRK6 in auditory and visual system development and is consistent with previously described SLITRK6-associated HL with myopia.
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.
Purpose Hereditary hearing loss is a genetically heterogeneous disorder, with more than 120 genes implicated in the non-syndromic forms. The genetic cause of non-syndromic hearing loss (NSHL) in a Chinese Han family was investigated, and the function of the identified mutation was characterized. Methods The family members were clinically evaluated. Targeted next-generation sequencing of 414 deafness-related genes was performed on the proband. The identified variants were validated in the family members of the proband using Sanger sequencing and PCR. The functional impacts of the variants on splicing were predicted using SpliceAI and MaxEntScan. Results Two compound heterozygous CDH23 mutations (c.7054+1G>A and c.4209+794_4825 del) were identified in a thirteen-month-old girl with NSHL. Sanger sequencing confirmed recessive inheritance, with each unaffected parent carrying a single heterozygous variant. The c.7054+1G>A variant is a canonical splice donor variant predicted to severely disrupt splicing (SpliceAI donor loss score: 0.99; MaxEntScan score reduced from 10.28 in the wild-type to 2.10 in the mutant, a 79.57% reduction). The c.4209+794_4825 del is a 6.45 kb heterozygous deletion encompassing exons 35–38, predicted to resulted in the in-frame skipping of exons 35–38. AlphaFold-based structural modeling revealed marked conformational changes in the mutant extracellular domain, supporting the hypothesis that these variants compromised CDH23-mediated tip-link formation and mechanotransduction. Conclusion We identified two novel compound heterozygous CDH23 mutations (c.7054+1G>A and c.4209+794_4825 del) in a Chinese Han family, expanding the known spectrum of CDH23 mutation and adding to the understanding of the genotype–phenotype correlations in NSHL.
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