Ultrarare missense and frameshift variants in the TECTA gene may involve tectorial membrane in familial Meniere disease

Abstract

ABSTRACTBackgroundMeniere’s disease (MD) is an inner ear disease defined by episodes of vertigo associated with sensorineural hearing loss initially affecting low- to medium frequencies, tinnitus, and aural fullness. Familial aggregation has been reported in 9-10% of MD patients showing, mostly, an autosomal dominant inheritance pattern with incomplete penetrance. However, familial MD is a genetically heterogeneous disorder and other inheritance patterns have been recently proposed, such as recessive and digenic inheritance involving rare variants in OTOG and MYO7A genes, respectively. In this study, a familial MD cohort was recruited to identify new candidate genes.MethodsExome sequencing was performed in 99 individuals (from 77 families) diagnosed with MD according to the diagnostic criteria defined by the Barany Society. Candidate variants were classified based on the ACMG/AMP guidelines, and their effects were evaluated by protein modeling. Standard audiometric evaluations were retrieved, and a case report was made of each family to assess the genotype-phenotype correlations.ResultsThe TECTA gene, which encodes α-tectorin, was highlighted as a candidate for four multicase MD families carrying rare missense heterozygous variants and a short deletion in this gene. Variants in α-tectorin were also found in two additional families with one MD patient and relatives with partial syndromes carrying a missense heterozygous variant and a short deletion. According to the predicted protein model, these variants could affect the stability of α-tectorin.ConclusionsSeveral MD families were identified carrying rare variants and deletions in the TECTA gene, which encodes one of the main proteins of the tectorial membrane (TM). The TM is an extracellular matrix localized over the sensory epithelium mediating the mechanical stimulation of cochlear hair cells, a critical role in the process of hearing. Modifications on the TM stability and the micromechanics involved in the sound-evoked motion of stereocilia might be involved in familial MD.