A Unique SLC26A4 Mutation Spectrum in a Mongolian Enlarged Vestibular Aqueduct Cohort via Whole-Exome Sequencing: A...

Enlarged vestibular aqueduct (EVA) is a common inner ear malformation that causes sensorineural hearing loss. It is frequently associated with pathogenic variants in the SLC26A4 gene. This study aimed to investigate the genetic basis of hearing loss in Mongolian patients with EVA. Whole-exome sequencing was performed in 19 Mongolian patients from 15 unrelated families diagnosed with EVA with or without cochlear incomplete partition type II. All patients underwent high-resolution computed tomography of the temporal bone to confirm the diagnosis. Biallelic SLC26A4 pathogenic variants were identified in all 15 families, achieving a 100% diagnostic yield. The most frequent variant was c.919-2A>G (40%), followed by c.2027T>A (23.3%) and c.1318A>T (16.7%). The spectrum of variants includes population-specific variants found in East Asians (c.919-2A>G), North Asians (c.2027T>A), and Southwest Asians (c.716T>A), suggesting a unique mutation spectrum in this Mongolian cohort characterized by variants prevalent across various Eurasian populations, which remains to be confirmed in larger studies. Furthermore, correlation analyses on multi-ethnic allele frequencies of biallelic SLC26A4 genotypes demonstrated positive correlations with deaf cohorts of East Asian, North Asian, Northeast Asian, and Western Asian groups. Digenic inheritance (with pathogenic variants in FOXI1, KCNJ10, or EPHA2) was not observed, and there was no clear genotype-phenotype correlation between specific SLC26A4 genotypes and hearing levels or inner ear malformations. This study provides a comprehensive overview of the genetic landscape of EVA in the Mongolian population. The identification of biallelic SLC26A4 pathogenic variants in all families underscores the clinical role of this gene in EVA pathogenesis. The observed pan-ethnic mutation spectrum likely reflects the genetic diversity resulting from historical migrations of Mongolians.