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Med."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the<jats:italic>TYR<\/jats:italic>(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 \u2018missing heritability\u2019 in OCA is well described, with ~25\u201330% 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<jats:italic>TYR<\/jats:italic>variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in<jats:italic>cis<\/jats:italic>alongside a pathogenic<jats:italic>TYR<\/jats:italic>variant in<jats:italic>trans<\/jats:italic>. We also show that homozygosity for the p.(Ser192Tyr)\/p.(Arg402Gln)<jats:italic>TYR<\/jats:italic>haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the<jats:italic>TYR<\/jats:italic>p.(Ser192Tyr)\/p.(Arg402Gln) in<jats:italic>cis<\/jats:italic>haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25\u201350%.<\/jats:p>","DOI":"10.1038\/s41525-021-00275-9","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T14:07:45Z","timestamp":1642514865000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Evidence that the Ser192Tyr\/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B)"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1122-8396","authenticated-orcid":false,"given":"Siying","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Sanchez-Breta\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S.","family":"Leslie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie B.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1494-2467","authenticated-orcid":false,"given":"N. 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