Different contribution of missense and loss-of-function variants to the genetic structure of familial and sporadic Meniere disease

Meniere disease (MD) is a chronic inner ear disorder with significant heritability. This study aims to compare the burden of rare high-and moderate-impact protein-coding variants in a MD cohort to determine whether the genetic burden in sporadic MD (SMD) overlaps familial MD (FMD), potentially revealing hidden inheritance in SMD. In this study 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 individuals with variants, inner-ear gene expression, and hearing and balance-related phenotypic annotations. In FMD patients, a higher accumulation of missense and loss-of-function variants was observed compared to SMD, particularly in genes associated with auditory and vestibular functions. GBA identified 269 enriched genes in SMD, with 31 annotated for inner ear phenotypes, while FMD had 432 genes with 51 pinpointed. Sporadic and FMD overlapped in 28.1% of the enriched genes, with ADGRV1, MEGF8 and MYO7A the most commonly found. In conclusion, SMD and FMD have a divergent genetic architecture. Both SMD and FMD have an overload of missense variants in stria vascularis and hair cell stereocilia genes that suggests different mechanisms in MD pathogenesis and a multiallelic-recessive inheritance pattern.