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Rare examples of late\u2010onset OTCD have also been described. Here, we describe an<jats:italic>OTC<\/jats:italic>promoter variant, c.\u2010106C&gt;A, in a conserved HNF4a binding site, identified in two male siblings in Family 1 whose first and only recognized episodes of severe hyperammonemia occurred at ages 14 and 39\u2009years, respectively. We identified the same<jats:italic>OTC<\/jats:italic>variant segregating in a large family with late\u2010onset OTCD with variable expressivity (Family 2). We show that this<jats:italic>OTC<\/jats:italic>promoter variant reduces expression &gt;5\u2010fold in a dual\u2010luciferase assay that tests promoter function. Addition of an upstream<jats:italic>OTC<\/jats:italic>enhancer increases expression of both the wild type and the c.\u2010106C&gt;A variant promoter constructs &gt;5\u2010fold with the mutant promoter still about fourfold lower than the wild type. Thus, in both contexts, the promoter variant results in substantially lower<jats:italic>OTC<\/jats:italic>expression. Under normal demand on urea cycle function,<jats:italic>OTC<\/jats:italic>expression in hemizygous males, although reduced, is sufficient to meet the demand for waste nitrogen excretion. However, in response to severe metabolic stress with attendant increased requirements on urea cycle function, the impaired promoter function results in inadequate<jats:italic>OTC<\/jats:italic>expression with resultant hyperammonemia. In the absence of precipitating events, hemizygotes with this allele are asymptomatic, explaining the late age of onset of hyperammonemia in affected individuals and the incomplete penetrance observed in some individuals in Family 2.<\/jats:p>","DOI":"10.1002\/jimd.12524","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T17:54:21Z","timestamp":1653328461000},"page":"710-718","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A promoter variant in the<i>OTC<\/i>gene associated with late and variable age of onset hyperammonemia"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5876-704X","authenticated-orcid":false,"given":"Sangwoo T.","family":"Han","sequence":"first","affiliation":[{"name":"Predoctoral Training Program in Human Genetics, McKusick\u2010Nathans Department of Genetic Medicine Johns Hopkins University School of Medicine Baltimore 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