Unveiling genetics of non-syndromic albinism using whole exome sequencing: A comprehensive study of TYR, TYRP1, OCA2 and MC1R genes in 17 families

Qaiser Zaman,Obaid Ur Rahman,Hamza Khan,Muhammad Idrees,Javeria Hussain,Nousheen Bibi,Eugene Lee,Raees Ahmad,Mohammad Shah Faisal,Kalsoom Sahar,Muhammad Imran Naseer,Bakht Tareen Khan,Mashal Ahmad,Muhammad Ismail Khan,Seung Woo Ryu,Angham Abdulrhman Abdulkareem,Sadeeda Sadeeda,Gauhar Rehman,Musharraf Jelani,Qaisar Jamal,Hammad Tufail Chaudhary,Jamshid Khan,Rafaqat Masroor ,Osama Muthaffar ,Muhammad Arif Khan ,Minita Shah

doi:10.1016/j.gene.2023.147986

Abstract

BackgroundOculocutaneous albinism (OCA) is a group of skin depigmentation disorders. Clinical presentation of OCA includes defects in melanocyte differentiation, melanin biosynthesis, and melanosome maturation and transport. ObjectivesA molecular diagnostics study of families presenting oculocutaneous albinism. MethodsIn this study, 17 consanguineous OCA families consisting of 93 patients were investigated. Whole Exome Sequencing (WES) of the index patient in each family were performed. Short listed variants of WES were Sanger validated for Mendelian segregation in obligate carriers and other available family members. Variant prioritization and pathogenicity were classified as per the criteria of American College Medical Genetics and Genomics (ACMG). Comparative computational modelling was performed to predict the potential damaging effect of the altered proteins. Results15 pathogenic variations: c.132 T > A, c.346C > T, c.488C > G, c.1037G > A in TYR, c.1211C > T, c.1441G > A, c.1706_1707insT, c.2020C > G, c.2402G > C, c.2430del, in OCA2, c.1067G > A in TYRP1 and c.451C > T, c.515G > T, c.766C > T, c.917G > A in MC1R genes were identified. Three variants in OCA2 gene were characterized: c.1706_1707insT, c.2430del, and c.2402G > C, all of which were not reported before in OCA families. ConclusionA few studies focusing on mutation screening of OCA patients have been reported before; however, this study has uniquely presents the Pakhtun ethnic population residing on the North-Western boarder. It explains that TYR, OCA2, TYRP1, and MC1R variations lead to non-syndromic OCA phenotype The overlapping phenotypes of OCA can precisely be diagnosed for its molecular pathogenicity using WES. This study recommends WES as a first-line molecular diagnostic tool, and provides a basis for developing customized genetic tests i.e. pre-marital screening to reduce the disease burden in the future generations.

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