Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B)
Author
Lin, S.
Sanchez-Bretaño, A.
Leslie, J. S.
Williams, K. B.
Lee, H.
Thomas, N. S.
Callaway, J.
Deline, J.
Ratnayaka, J. A.
Baralle, D.
Schmitt, M. A.
Norman, C. S.
Hammond, S.
Harlalka, G. V.
Ennis, S.
Cross, H. E.
Wenger, O.
Crosby, A. H.
Baple, E. L.
Self, J. E.
Date
2022-01-13Journal
NPJ genomic medicineType
Journal ArticlePublisher
PubMed CentralDOI
10.1038/s41525-021-00275-9Rights
© 2022. The Author(s).Metadata
Show full item recordAbstract
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%.