| Autor: |
Siying Lin, Aida Sanchez-Bretaño, Joseph S. Leslie, Katie B. Williams, Helena Lee, N. Simon Thomas, Jonathan Callaway, James Deline, J. Arjuna Ratnayaka, Diana Baralle, Melanie A. Schmitt, Chelsea S. Norman, Sheri Hammond, Gaurav V. Harlalka, Sarah Ennis, Harold E. Cross, Olivia Wenger, Andrew H. Crosby, Emma L. Baple, Jay E. Self |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
npj Genomic Medicine, Vol 7, Iss 1, Pp 1-11 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2056-7944 |
| DOI: |
10.1038/s41525-021-00275-9 |
| Popis: |
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%. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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