{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:12:02Z","timestamp":1760238722538,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,8,22]],"date-time":"2020-08-22T00:00:00Z","timestamp":1598054400000},"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","R56DC011803"],"award-info":[{"award-number":["R01DC016295","R56DC011803"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>We report the underlying genetic causes of prelingual hearing loss (HL) segregating in eight large consanguineous families, ascertained from the Punjab province of Pakistan. Exome sequencing followed by segregation analysis revealed seven potentially pathogenic variants, including four novel alleles c.257G&gt;A, c.6083A&gt;C, c.89A&gt;G, and c.1249A&gt;G of CLPP, CDH23, COL4A5, and LARS2, respectively. We also identified three previously reported HL-causing variants (c.4528C&gt;T, c.35delG, and c.1219T&gt;C) of MYO15A, GJB2, and TMPRSS3 segregating in four families. All identified variants were either absent or had very low frequencies in the control databases. Our in silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Variants identified in MYO15A, GJB2, TMPRSS3, and CDH23 were classified as \u201cpathogenic\u201d or \u201clikely pathogenic\u201d, while the variants in CLPP and LARS2 fall in the category of \u201cuncertain significance\u201d based on the American College of Medical Genetics and Genomics\/Association for Molecular Pathology (ACMG\/AMP) variant pathogenicity guidelines. This paper highlights the genetic diversity of hearing disorders in the Pakistani population and reports the identification of four novel mutations in four HL families.<\/jats:p>","DOI":"10.3390\/genes11090978","type":"journal-article","created":{"date-parts":[[2020,8,23]],"date-time":"2020-08-23T21:28:06Z","timestamp":1598218086000},"page":"978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Novel Mutations in CLPP, LARS2, CDH23, and COL4A5 Identified in Familial Cases of Prelingual Hearing Loss"],"prefix":"10.3390","volume":"11","author":[{"given":"Saba","family":"Zafar","sequence":"first","affiliation":[{"name":"Institute of Molecular Biology &amp; Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohsin","family":"Shahzad","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafaqat","family":"Ishaq","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"University Institute of Biochemistry &amp; Biotechnology, PMAS-Arid Agriculture University, Rawalpindi 46000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayesha","family":"Yousaf","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology &amp; Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3648-6965","authenticated-orcid":false,"given":"Rehan S.","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology &amp; Biotechnology, Bahauddin Zakariya University, Multan 60800, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javed","family":"Akram","sequence":"additional","affiliation":[{"name":"University of Health Sciences, Lahore 54600, 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 Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saima","family":"Riazuddin","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1056\/NEJMra050700","article-title":"Newborn hearing screening\u2014A silent revolution","volume":"354","author":"Morton","year":"2006","journal-title":"N. 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