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Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the  TYR  (tyrosinase) gene which encodes the critical and rate-limiting enzyme in melanin synthesis. It is the most common OCA subtype found in Caucasians, accounting for ~50% of cases worldwide. The apparent ‘missing heritability’ in OCA is well described, with ~25–30% of clinically diagnosed individuals lacking two clearly pathogenic variants. Here we undertook empowered genetic studies in an extensive multigenerational Amish family, alongside a review of previously published literature, a retrospective analysis of in-house datasets, and tyrosinase activity studies. Together this provides irrefutable evidence of the pathogenicity of two common  TYR  variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in  cis  alongside a pathogenic  TYR  variant in  trans . We also show that homozygosity for the p.(Ser192Tyr)/p.(Arg402Gln)  TYR  haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the  TYR  p.(Ser192Tyr)/p.(Arg402Gln) in  cis  haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25–50%.

Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B)