{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:07:02Z","timestamp":1758845222323,"version":"3.44.0"},"reference-count":58,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T00:00:00Z","timestamp":1757721600000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004681","name":"Higher Education Commission, Pakistan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004681","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Inherited eye disorders are a significant cause of vision loss worldwide. According to the World Health Organization (WHO) estimates approximately 2.2 billion people have some degree of vision loss, but a significant proportion of these are blind since early childhood. Due to poor infrastructure for genetic diagnosis, many affected families remain genetically unexplained in underdeveloped countries, including Pakistan.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we utilized homozygosity mapping and exome sequencing to identify the genetic basis of the vision loss in four Kashmiri families that were presented with different types of eye disorders. We also performed quantitative reverse transcriptase\u2010PCR (qRT\u2010PCR) and measured the relative mRNA abundance of <jats:italic>ALMS1<\/jats:italic> in blood cells of patients, carrier parents, and a healthy control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genetic analysis identified a novel homozygous 4 base pair frameshift deletion c.5747_5750del; p.(Ala1916Glufs*21) in <jats:italic>ALMS1<\/jats:italic> in a family affected with Alstrom syndrome (AS), and already known variants were identified (CNGA3; c.1315C&gt;T; p.(Arg439Trp) and <jats:italic>FYCO1<\/jats:italic>; c.2206C&gt;T; p.(Gln736*) and c.3150\u2009+\u20091G&gt;T; p.(?)) in the remaining three families. The variant identified in the <jats:italic>ALMS1<\/jats:italic> gene is predicted to activate nonsense mediated mRNA decay (NMD). Comparison of relative mRNA abundance of <jats:italic>ALMS1<\/jats:italic> in patient\u2010specific cells harboring c.5747_5750del negates the NMD activation. The results indicated the absence of NMD in patient\u2010derived cells and therefore support the formation of a truncated ALMS1 protein in the patients with the c.5747_5750del variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We expanded the mutation spectrum of <jats:italic>ALMS1<\/jats:italic> but identified known variants in <jats:italic>FYCO1<\/jats:italic> and <jats:italic>CNGA3<\/jats:italic> genes. We also compiled the currently known mutations in these genes to establish genotype\u2013phenotype correlation.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70141","type":"journal-article","created":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T08:20:23Z","timestamp":1757751623000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Variants in Four Families With Inherited Eye Disorders by Whole Exome Sequencing"],"prefix":"10.1002","volume":"13","author":[{"given":"Afeefa","family":"Jarral","sequence":"first","affiliation":[{"name":"Department of Biotechnology Mirpur University of Science and Technology (MUST)  Mirpur Pakistan"},{"name":"Department of Biochemistry Quaid\u2010I\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabia","family":"Basharat","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Quaid\u2010I\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sundus","family":"Sajid","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Quaid\u2010I\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kinza","family":"Arshad","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Quaid\u2010I\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Imran","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biotechnology Mirpur University of Science and Technology (MUST)  Mirpur Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad","family":"Ansar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Quaid\u2010I\u2010Azam University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,13]]},"reference":[{"issue":"14","key":"e_1_2_8_2_1","article-title":"FYCO1 Mutation Hotspot in Congenital Cataract","volume":"53","author":"Abouzeid H.","year":"2012","journal-title":"Investigative Ophthalmology & Visual Science"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43042-022-00272-2"},{"key":"e_1_2_8_5_1","first-page":"183","article-title":"Identification of Novel Mutation in CNGA3 Gene by Whole\u2010Exome Sequencing and In\u2010Silico Analyses for Genotype\u2010Phenotype Assessment With Autosomal Recessive Achromatopsia in Pakistani Families","volume":"69","author":"Arshad M. 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