Targeted Analysis of Whole Exome Sequencing Data Identifies Biologically Plausible Causal Variants in Genetically Unresolved Oculocutaneous Albinism Patients From India
- 1University of Calcutta
Abstract
BackgroundOculocutaneous 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.
MethodsWhole 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.
ResultsIn 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.
ConclusionsOur 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.
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BibTeX
@misc{dutta2026targeted,
title = {{Targeted Analysis of Whole Exome Sequencing Data Identifies Biologically Plausible Causal Variants in Genetically Unresolved Oculocutaneous Albinism Patients From India}},
author = {T. Dutta and D. Dey and A. Saha and S. Banerjee and K. Ray and M. Sengupta},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.26362137},
url = {https://www.medrxiv.org/content/10.64898/2026.09.03.26362137v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Targeted Analysis of Whole Exome Sequencing Data Identifies Biologically Plausible Causal Variants in Genetically Unresolved Oculocutaneous Albinism Patients From India
AU - T. Dutta
AU - D. Dey
AU - A. Saha
AU - S. Banerjee
AU - K. Ray
AU - M. Sengupta
PY - 2026
DA - 2026/09/03
PB - medRxiv
DO - 10.64898/2026.09.03.26362137
UR - https://www.medrxiv.org/content/10.64898/2026.09.03.26362137v1
AB - BackgroundOculocutaneous 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. MethodsWhole 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. ResultsIn 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. ConclusionsOur 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.
ER -