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Identification 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 <jats:italic>GJB2-GJB6<\/jats:italic> mutations, we performed whole exome sequencing in 32 unrelated Argentinean families. Mutations were detected in 16 known deafness genes in 20 patients: <jats:italic>ACTG<\/jats:italic>1, <jats:italic>ADGRV<\/jats:italic>1 (<jats:italic>GPR<\/jats:italic>98), <jats:italic>CDH<\/jats:italic>23, <jats:italic>COL4<\/jats:italic>A3, <jats:italic>COL<\/jats:italic>4A5, <jats:italic>DFNA<\/jats:italic>5 (<jats:italic>GSDDE<\/jats:italic>), <jats:italic>EYA<\/jats:italic>4, <jats:italic>LARS<\/jats:italic>2, <jats:italic>LOXHD<\/jats:italic>1, <jats:italic>MITF<\/jats:italic>, <jats:italic>MYO<\/jats:italic>6, <jats:italic>MYO<\/jats:italic>7A, <jats:italic>TECTA, TMPRSS<\/jats:italic>3, <jats:italic>USH<\/jats:italic>2<jats:italic>A<\/jats:italic> and <jats:italic>WSF<\/jats:italic>1<jats:italic>.<\/jats:italic> Notably, 11 variants affecting 9 different non-<jats:italic>GJB2<\/jats:italic> genes resulted novel: c.12829C\u2009&gt;\u2009<jats:italic>T, p.(Arg4277*) in ADGRV1; c.337del, p.(Asp109*) and c.3352del, p.(Gly1118Alafs*7) in CDH23; c.3500G<\/jats:italic>\u2009&gt;\u2009<jats:italic>A, p.(Gly1167Glu) in COL4A3; c.1183C<\/jats:italic>\u2009&gt;\u2009<jats:italic>T, p.(Pro395Ser) and c.1759C<\/jats:italic>\u2009&gt;\u2009<jats:italic>T, p.(Pro587Ser) in COL4A5; c.580<\/jats:italic>\u2009+\u2009<jats:italic>2\u00a0T<\/jats:italic>\u2009&gt;\u2009<jats:italic>C in EYA4; c.1481dup, p.(Leu495Profs*31) in LARS2; c.1939\u00a0T<\/jats:italic>\u2009&gt;\u2009<jats:italic>C, p.(Phe647Leu), in MYO6; c.733C<\/jats:italic>\u2009&gt;\u2009<jats:italic>T, p.(Gln245*) in MYO7A and c.242C<\/jats:italic>\u2009&gt;\u2009<jats:italic>G, p.(Ser81*) in TMPRSS3 genes.<\/jats:italic> To predict the effect of these variants, novel protein modeling and protein stability analysis were employed. These results highlight the value of whole\u00a0exome\u00a0sequencing\u00a0to identify candidate variants, as well as bioinformatic strategies to infer their pathogenicity.<\/jats:p>","DOI":"10.1038\/s41598-021-04081-2","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T11:03:21Z","timestamp":1641553401000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2985-4790","authenticated-orcid":false,"given":"Paula I.","family":"Buonfiglio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-5418","authenticated-orcid":false,"given":"Carlos D.","family":"Bruque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanesa","family":"Lotersztein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2956-2907","authenticated-orcid":false,"given":"Leonela","family":"Luce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5026-5486","authenticated-orcid":false,"given":"Florencia","family":"Giliberto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9860-8457","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Menazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Francipane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibiana","family":"Paoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Goldschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-0311","authenticated-orcid":false,"given":"Ana Bel\u00e9n","family":"Elgoyhen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5283-4726","authenticated-orcid":false,"given":"Viviana","family":"Dalam\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,7]]},"reference":[{"key":"4081_CR1","volume-title":"GeneReviews","author":"AE Shearer","year":"1999","unstructured":"Shearer, A. 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