Rare Coding Variants in Patients with Non-Syndromic Vestibular Dysfunction.

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere's disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere's disease, and 38 European-American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, , , and , have knockout mouse models for vestibular dysfunction. Moreover, and were expressed in human vestibular tissues. Rare variants within , , and were each identified in three adult patients with Meniere's disease. Additionally, an variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease.