Replication of missense OTOG gene variants in a Brazilian cohort of Meniere's Disease

Menieres Disease (MD) is a chronic inner ear disorder defined by recurring episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or fullness in the ear. Its prevalence varies by region and ethnicity, with scarce epidemiological data in Brazilian population. Although most MD cases are sporadic, Familial MD (FMD) is observed in 5% to 20% of European cases. By exome sequencing, we have found a rare missense variant in the OTOG gene in a Brazilian MD individual with probable European ancestry (chr11:17599671C>T), which was previously reported in a Spanish cohort. Two additional rare missense heterozygous OTOG variants were found in the same proband. Splice Site analysis showed that chr11:17599671C>T may lead to substantial changes generating exonic cis regulatory elements, and protein modelling revealed structural changes in the presence of chr11:17599671C>T, chr11:17576581G>C and chr11:17594108C>T, predicted to highly destabilize protein structure. These findings indicate that missense variants may have an additive effect leading to an unstable Otogelin and support OTOG gene as a key player in the MD pathophysiology.