Molecular Characterization of Oculocutaneous Albinism in Pakhtun Families Reveals Recurrent Variants in TYR and OCA2

Abstract

Background: Oculocutaneous albinism (OCA) is a rare, genetically heterogeneous disorder characterized by impaired melanin biosynthesis and distribution in the skin, hair, and eyes. The severity of dermatological and ophthalmological manifestations varies depending on the underlying genetic defect. Methods: Five unrelated consanguineous families with multiple individuals affected by OCA were recruited from Khyber Pakhtunkhwa, Pakistan. Whole-exome sequencing (WES) was performed for the probands, followed by Sanger sequencing to confirm variant segregation. Variants were prioritized using the in-house VARDIGS pipeline and evaluated through population databases (gnomAD, ClinVar, HGMD), computational prediction tools (SIFT, PolyPhen-2, CADD, MutationTaster), and interpretation platforms (Franklin, VarSome, GeneBe). Final classification was performed according to ACMG guidelines. Results: Clinical evaluation revealed hypopigmented skin and hair, translucent irides, nystagmus, photophobia, and reduced visual acuity in affected individuals. Molecular analysis identified four recurrent pathogenic and one likely pathogenic variants in TYR and OCA2. Three variants were detected in TYR, including a frameshift variant c.216delA (p.Val74TrpfsTer46), observed for the first time in Pakistani patients, a missense variant c.132T>A (p.Ser44Arg), and a nonsense variant c.346C>T (p.Arg116Ter). Two variants in OCA2 including a missense variant c.1211C>T (p.Thr404Met) and a frameshift splice region variant c.2430delC (p.Phe810LeufsTer7) were identified in OCA2. Sanger sequencing confirmed co-segregation of all variants with the disease phenotype in respective families. In silico analyses consistently supported their pathogenicity with the exception of last OCA2 variant. Conclusion: This study reports five previously described variants, including three pathogenic in TYR, one pathogenic and one likely pathogenic OCA2 variants in consanguineous families of Pakhtun ethnicity, thereby expanding the mutational spectrum of OCA in the Pakistani population. The recurrence of these variants underscores the significant contribution of TYR and OCA2 to OCA in this region and highlights the impact of consanguinity. These findings have important implications for genetic counseling, carrier screening, and informed family planning.