An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European descendant population

Abstract

Abstract Meniere's disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, coding regions with high constraint (low density of rare variants) in OTOG coding sequence in Non-Finnish European (NFE) were identified. Missense variants (AF<0.01) were selected from a 100 FMD patients’ cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios (OR) were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with two variants (rs61978648, rs61736002) shared by 5 individuals and one variant (rs117315845) shared by 2 individuals. The results confirm the observed enrichment of OTOGrare missense variants in FMD. Furthermore, 8 variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions and may have a founder effect and explain the burden of FMD in the European population.