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

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    URI
    https://rde.dspace-express.com/handle/11287/622393
    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
    2022-01-13
    Journal
    NPJ genomic medicine
    Type
    Journal Article
    Publisher
    PubMed Central
    DOI
    10.1038/s41525-021-00275-9
    Rights
    © 2022. The Author(s).
    Metadata
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    Abstract
    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%.
    Citation
    NPJ Genom Med. 2022 Jan 13;7(1):2. doi: 10.1038/s41525-021-00275-9.
    Publisher URL
    https://doi.org/10.1038/s41525-021-00275-9
    Note
    The article is available via Open Access. Click on the 'Additional link' above to access the full-text.
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    • 2022 Eastern publications
    • Genetics and genomics

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