DNA Variations in Oculocutaneous Albinism: An Updated Mutation List and Current Outstanding Issues in Molecular Diagnostics

ABSTRACT Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA caused by mutations in TYR (OCA‐1), OCA2 (OCA‐2), TYRP1 (OCA‐3), or SLC45A2 (OCA‐4). Here we report 22 novel mutations in the OCA genes; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and eight from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions as a supplement. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 26% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature‐sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation. Isolated oculocutaneous albinism (OCA) is an autosomal recessive condition causing low vision and hypopigmentation. The article provides a mutation update for the OCA genes and discusses several challenging aspects of OCA molecular diagnostics, including the temperature sensitive TYR p.R402Q mutation, OCA‐1 subtyping and the presence of a substantial minority of affected individuals with apparent missing heritability. A comprehensive list of previously reported mutations is provided as supplementary material, and includes collated ethnicity information, carrier frequencies, and in silico pathogenicity predictions.