{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:34:33Z","timestamp":1760236473317,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R01DC016295"],"award-info":[{"award-number":["R01DC016295"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Hearing loss (HL) is the most common neurosensory defect in humans that affects the normal communication. Disease is clinically and genetically heterogeneous, rendering challenges for the molecular diagnosis of affected subjects. This study highlights the phenotypic and genetic complexity of inherited HL in a large consanguineous Pakistan kindred. Audiological evaluation of all affected individuals revealed varying degree of mild to profound sensorineural HL. Whole exome (WES) of four family members followed by Sanger sequencing revealed candidate disease-associated variants in five known deafness genes: GJB2 (c.231G&gt;A; p.(Trp77 *)), SLC26A4 (c.1337A&gt;G; p.(Gln446Arg)), CDH23 (c.2789C&gt;T; p.(Pro930Leu)), KCNQ4 (c.1672G&gt;A; p.(Val558Met)) and MPDZ (c.4124T&gt;C; p.(Val1375Ala)). All identified variants replaced evolutionary conserved residues, were either absent or had low frequencies in the control databases. Our in silico and 3-Dimensional (3D) protein topology analyses support the damaging impact of identified variants on the encoded proteins. However, except for the previously established \u201cpathogenic\u201d and \u201clikely pathogenic\u201d categories for the c.231G&gt;A (p.(Trp77 *)) allele of GJB2 and c.1377A&gt;G (p.(Gln446Arg)) of SLC26A4, respectively, all the remaining identified variants were classified as \u201cuncertain significance\u201d based on the American College of Medical Genetics and Genomics\/Association for Molecular Pathology (ACMG\/AMP) variant pathogenicity guidelines. Our study highlights the complexity of genetic traits in consanguineous families, and the need of combining the functional studies even with the comprehensive profiling of multiple family members to improve the genetic diagnosis in complex inbred families.<\/jats:p>","DOI":"10.3390\/genes12121940","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T20:29:27Z","timestamp":1638304167000},"page":"1940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification and Computational Analysis of Rare Variants of Known Hearing Loss Genes Present in Five Deaf Members of a Pakistani Kindred"],"prefix":"10.3390","volume":"12","author":[{"given":"Irum Badshah","family":"Saleem","sequence":"first","affiliation":[{"name":"Department of Bioinformatics and Biotechnology, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2395-7721","authenticated-orcid":false,"given":"Muhammad Shareef","family":"Masoud","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biotechnology, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Qasim","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biotechnology, Government College University, Faisalabad 38000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, Quaid-e-Azam University, Islamabad 46000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2914-4502","authenticated-orcid":false,"given":"Zubair M.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.gene.2018.01.027","article-title":"Genetic basis of hearing loss in Spanish, Hispanic and Latino populations","volume":"647","author":"Mittal","year":"2018","journal-title":"Gene"},{"key":"ref_2","unstructured":"World Health Organization (2018). 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