Paula I. Buonfglio, Carlos D. Bruque, Vanesa Lotersztein, Leonela Luce, FlorenciaGiliberto, Sebastián Menazzi, Liliana Francipane, Bibiana Paoli, ErnestoGoldschmidt, Ana Belén Elgoyhen, Viviana Dalamón
Hearing loss is a heterogeneous disorder. Identifcation of causative mutations is demanding due to genetic heterogeneity. In this study, we investigated the genetic cause of sensorineural hearing loss in patients with severe/profound deafness. After the exclusion of GJB2-GJB6 mutations, we performed whole exome sequencing in 32 unrelated Argentinean families. Mutations were detected in 16 known deafness genes in 20 patients: ACTG1, ADGRV1 (GPR98), CDH23, COL4A3, COL4A5, DFNA5 (GSDDE), EYA4, ARS2, LOXHD1, MITF, MYO6, MYO7A, TECTA, TMPRSS3, USH2A and WSF1. Notably, 11 variants afecting 9 diferent non-GJB2 genes resulted novel: c.12829C>T, p.(Arg4277) in ADGRV1; c.337del, p.(Asp109) and c.3352del, p.(Gly1118Alafs7) in CDH23; c.3500G>A, p.(Gly1167Glu) in COL4A3; c.1183C>T, p.(Pro395Ser) and c.1759C>T, p.(Pro587Ser) in COL4A5; c.580 + 2T>C in EYA4; c.1481dup, p.(Leu495Profs31) in LARS2; c.1939T>C, p.(Phe647Leu), in MYO6; c.733C>T, p.(Gln245) in MYO7A and c.242C>G, p.(Ser81) in TMPRSS3 genes. To predict the efect of these variants, novel protein modeling and protein stability analysis were employed. These results highlight the value of whole exome sequencing to identify candidate variants, as well as bioinformatic strategies to infer their pathogenicity.