Hearing Loss and Enlarged Vestibular Aqueduct (EVA) in a Patient Negative for Canonical EVA Genes: Potential Role of SCD5

Biallelic pathogenic variants in SLC26A4 cause hearing loss with an Enlarged Vestibular Aqueduct (EVA), but approximately 50% of EVA patients in Caucasian cohorts remain genetically unresolved, suggesting the presence of overlooked variants at canonical EVA loci or the involvement of non-canonical genes. Here, we investigated a 42-year-old Caucasian male presenting with bilateral mixed hearing loss and EVA who tested negative for established EVA genes but harbored two heterozygous variants of uncertain significance: Repressor Element 1-Silencing Transcription Factor (REST) c.3272_3274delAAG (p.E1091del) and Stearoyl-CoA Desaturase 5 (SCD5) c.452T>G (p.F151C). Segregation analysis revealed that the variants were inherited from normal-hearing parents, prompting whole-genome sequencing, which ruled out causative deep intronic or promoter variants at the EVA loci SLC26A4, FOXI1, and KCNJ10, as well as in the coding regions of the genes encoding SLC26A4-interacting proteins EPHA2, IQGAP1, and AP-2. Functional testing showed that while the REST variant did not affect cell viability or transcriptional regulation, the SCD5 variant significantly reduced cell viability and induced robust intracellular accumulation of reactive oxygen species (ROS), triggering compensatory activation of the Nrf2/SOD antioxidant axis, thereby supporting pathogenicity. This study expands the phenotypic spectrum of SCD5 by suggesting a novel association between this gene and EVA for the first time and highlights the potential role of oxidative stress in inner ear malformations.