Haplotype‐Based Analysis of <i>OCA2</i> Variants in Oculocutaneous Albinism

ABSTRACT OCA2, a melanosome transmembrane spanning protein, functions to regulate melanosomal pH, optimizing production of melanin pigment. OCA2 is one of eight non‐syndromic autosomal recessive oculocutaneous albinism (OCA) loci and is the second most common cause of OCA worldwide. Genome wide association studies (GWAS) have identified OCA2 coding and regulatory variants linked to common skin and eye color pigment variation, skin cancer susceptibility, and retinal pigment epithelium tissue metrics. Within a cohort of 106 OCA2 probands with two biallelic OCA2 variants, a total of 74 distinct OCA2 rare variants were identified (11 large structural, 17 small indel/frameshift, 12 splice site, and 34 missense coding variants). Phase‐validated haplotypes, comprised of both OCA2 common pigmentation trait GWAS alleles and rare variants, were obtained for 95/106 probands. In total, 41 distinct multi‐allele OCA2 haplotypes were identified with 27 haplotypes containing either rs1800404‐A and/or rs12913832‐G alleles, each of which is known to reduce correct isoform splicing or gene expression by ~20%. These results find that common GWAS alleles with known OCA2 functional impact are present on haplotypes with variants of unknown significance in OCA2 probands and highlight the need for haplotype‐based analysis at the OCA2 locus in addition to individual variant pathogenic assessment.