Reevaluation of Enlarged Vestibular Aqueduct.

Importance: Enlarged vestibular aqueduct (EVA), the most prevalent inner ear malformation causing hearing loss (HL) in various populations, is predominantly genetically mediated. Despite advancements in genetic diagnostics, the comprehensive phenotypic and genotypic spectrum of EVA remains insufficiently characterized.

Objectives: To characterize the natural history, clinical outcomes, phenotype, and genotype of EVA.

Design, setting, and participants: This single-center, longitudinal, retrospective cohort study was conducted from March 2003 to October 2022, with follow-up until July 1, 2024. Patients with EVA who were seeking medical advice at the Chinese PLA General Hospital were included.

Main outcomes and measures: This study presents a 21-year longitudinal analysis of Chinese patients with EVA, providing a systematic analysis of the natural history, phenotypic diversity, and molecular etiology of EVA.

Results: Of 2774 patients, 1453 (52.4%) were female individuals, and the median (range) age was 8 (4 months to 45 years) years. This study identified that 124 of 341 patients (36.36%) with EVA received passing newborn hearing screening results, while 375 of 597 (62.8%) received a diagnosis through combined audiological and radiological assessments. Recurrent vertigo (256 of 597 [42.9%]) and goiter (38 of 597 [6.4%]) were common comorbidities. Genetic analysis revealed that 2661 of 2774 patients (95.9%) carried biallelic SLC26A4 variants, with 70 (2.5%) attributable to copy number variants and 13 (0.5%) to a deep-intronic variant (c.304 + 941C>T) that affected splicing. A de novo heterozygous FOXI1 variant (c.483_485delCAA) was identified in an EVA family, indicating an autosomal dominant inheritance pattern. A stepped genomic analysis strategy was associated with an improved molecular diagnosis rate of 95.9%, highlighting the necessity of comprehensive genetic testing beyond traditional coding regions.

Conclusions and relevance: The results of this cohort study underscore the importance of periodic hearing surveillance and tailored genetic counseling for patients with EVA, offering substantial implications for prevention, management, and future gene therapy approaches. This study provides an extensive phenotypic and genotypic characterization of EVA, potentially advancing an understanding of its molecular underpinnings and clinical heterogeneity.