Prediction and interpretation of rare missense variant in OTOG associated with hearing loss

Abstract

OTOG encodes for otogelin, a component of the tectorial membrane. This gene is associated with nonprogressive mild-to-moderate hearing loss. However, no studies have yet identified the association between OTOG variation and severe-to-profound hearing loss. Therefore, to address this issue, a family-based whole-exome sequencing strategy (WES) was carried out. Two unrelated Iranian families with non-syndromic hearing loss were identified, and WES was conducted on one selected candidate from each family. As a result, a rare homozygous missense variant, OTOG (c.C2383T:p.R795C), was detected in both of the subjected probands, and segregation analysis confirmed the c.C2383T variant in seven cases of severe-to-profound hearing loss. Additionally, the results from the protein modeling demonstrated that the altered position of a few disulfide bonds in the TIL domain may have a deleterious impact on protein stability and normal functionality. In conclusion, it seems that the homozygosity of the OTOG c.C2383T mutation sheds light on hearing loss pathobiology. Nevertheless, further studies are required to unravel the precise function of OTOG mutation, which is potentially associated with severe-to-profound hearing loss.

Keywords: Homozygous OTOG; Inherited non-syndromic hearing loss; Molecular diagnosis; Next-generation sequencing; Protein modeling.