Targeted Analysis of Whole Exome Sequencing Data Identifies Biologically Plausible Causal Variants in Genetically Unresolved Oculocutaneous Albinism Patients From India
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Background
Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder characterized by hypopigmentation and visual abnormalities. Despite eight established OCA-associated loci, some clinically diagnosed patients remain genetically unresolved, suggesting contributions from additional pigmentation-associated genes.
Methods
Whole exome sequencing was performed in clinically diagnosed OCA patients lacking pathogenic variants or carrying a single heterozygous variant in known OCA genes (OCA1–OCA8). Targeted analysis of 809 pigmentation-associated genes involved in melanogenesis, melanosomal transport, melanocyte differentiation, stem-cell maintenance, and pigmentation phenotypes was conducted. Variants were prioritized based on ACMG classification, rarity, predicted coding consequence, and biological relevance to pigmentation pathways.
Results
In 5 patients with missing heritability, ACMG/Varsome/Ensembl Variant Effect Predictor-classified pathogenic/likely pathogenic rare variants were identified in pigmentation-associated genes including RAB38, MYO5A , and DOCK7 , involved in melanosome biogenesis/maturation, transport, or pigmentation abnormalities. Potential disease-causing variants were also identified in BMPR1B, MYC, POLG, GNA11 , and GGT1 , which lack established roles in melanin biosynthesis or distribution but may contribute to pigmentation based on emerging evidence. Two patients harboured prioritised variants in multiple pigmentation-associated genes. Notably, 3 of 5 patients harboured previously identified changes in known OCA-causing genes in heterozygous condition, suggesting cumulative modifier or digenic/oligogenic contributions.
Conclusions
Our findings broaden the spectrum of candidate pigmentation-associated variants in unresolved OCA cases and support possible oligogenic or modifier-driven mechanisms underlying phenotypic heterogeneity. However, these findings are hypothesis-generating and require functional validation.
