Different Contribution of Missense and Loss-of-Function Variants to the Genetic Structure of Familial and Sporadic Meniere Disease

Abstract

Meniere disease (MD) is a chronic inner ear disorder with significant heritability. This study compares the burden of rare highand moderate-impact coding variants in an MD cohort to determine whether genetic burden in sporadic MD (SMD) overlaps familial MD (FMD), potentially revealing hidden inheritance in SMD. Exome sequencing identified rare variants in unrelated FMD (N = 93) and SMD (N = 287) patients. Gene Burden Analysis (GBA) was performed, and candidate genes were prioritized using the number of variant carriers, inner-ear expression, and hearing/balance-related phenotypic annotations. FMD patients showed higher accumulation of missense and loss-of-function variants than SMD, especially in genes linked to auditory and vestibular function. GBA identified 269 enriched genes in SMD, with 31 annotated for inner ear phenotypes, while FMD had 432 with 51 pinpointed. Sporadic and FMD overlapped in 28.1% of enriched genes, with ADGRV1, MEGF8, and MYO7A most commonly shared. Auditory brainstem responses from knockout mouse models supported hearing loss of three novel MD candidate genes (NIN, CCDC88C, and ANKRD24), consistent with patient hearing profiles. In conclusion, SMD and FMD have a divergent genetic architecture. The enrichment of missense variants in stria vascularis and hair cell stereocilia genes supports distinct pathogenic mechanisms and a multiallelic-recessive inheritance pattern in MD.