Identification of Pathogenic Variants in African Individuals with Oculocutaneous Albinism Type 2 Negative for the Common 2.7 kb Deletion Variant

Abstract

Oculocutaneous albinism is a group of rare, inherited pigmentation disorders characterised by hypopigmentation of the hair and skin and impaired vision. The most common form of albinism is oculocutaneous albinism type 2 (OCA2) which has a high prevalence in African populations. The most common cause of OCA2 in African individuals is a 2.7 kb intragenic deletion variant in the OCA2 gene, and in the Southern African population, it accounts for 78% of all OCA2 pathogenic variants. The aim of this study was to identify pathogenic variants in African individuals with OCA2 that were negative or heterozygous for the common African OCA2 2.7 kb deletion. Whole exome sequencing (WES) data was available for eight individuals who were clinically diagnosed with OCA2 and referred to the Molecular Genetics Diagnostic Laboratory, Division of Human Genetics, NHLS for genetic testing. The WES data was analysed to identify possible pathogenic variants in the OCA2 gene, besides the 2.7kb deletion, and variants in other OCA-related genes (where no variants were identified in the OCA2 gene). Variants were annotated using Ensembl’s Variant Effect Predictor and then filtered based on functionality and minor allele frequency. Frameshift, missense, non-synonymous and splice site variants with a low minor allele frequency (MAF<5%) were prioritised. Prioritised variants were classified according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines. This study identified a likely pathogenic variant, NM_000275.3: c.1239+2T>A, in the OCA2 gene and a variant of uncertain significance, NM_000550.3: c. 291G>C, in the TYRP1 gene in separate patients. These results suggest that WES is a useful technique for identifying variants in individuals with albinism, a disorder that exhibits locus heterogeneity. Limitations regarding copy number analysis using WES data, and difficulties encountered in interpretation of variants due to lack of population data and functional studies, should be addressed in future research. Identification of these potentially clinically significant variants contributes to our understanding of the variant profile of the OCA2 phenotype in individuals of African descent.