{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T14:09:14Z","timestamp":1793196554537,"version":"4.5.0"},"reference-count":64,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002738","name":"Assistance Publique - H\u00f4pitaux de Paris","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X\u2010linked <jats:italic>OTC<\/jats:italic> gene. Phenotype\u2010genotype correlations are well understood in males but still poorly known in females. Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation, and <jats:italic>OTC<\/jats:italic> gene sequencing to genetic counseling in heterozygous females. Twenty two percent of the heterozygous females were clinically affected, with episodic (11%), chronic (7.5%), or neonatal forms of the disease (3.5%). Overall mortality rate was 4%. OTC activity, ranging from 0% to 60%, did not correlate with phenotype at the individual level. Analysis of multiple samples from 4 mutant livers showed intra\u2010hepatic variability of OTC activity and X inactivation profile (range of variability: 30% and 20%, respectively) without correlation between both parameters for 3 of the 4 livers. Ninety disease\u2010causing variants were found, 27 of which were novel. Mutations were classified as \u201cmild\u201d or \u201csevere,\u201d based on male phenotypes and\/or in silico prediction. In our cohort, a serious disease occurred in 32% of females with a severe mutation, compared to 4% in females with a mild mutation (odds ratio\u00a0=\u00a01.365; <jats:italic>P<\/jats:italic>\u00a0=\u00a01.6e\u201006). These data should help prenatal diagnosis for heterozygous females and genetic counseling after fortuitous findings of OTC variants in pangenomic sequencing.<\/jats:p>","DOI":"10.1002\/jimd.12404","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T14:46:22Z","timestamp":1621521982000},"page":"1235-1247","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["<scp>OTC<\/scp> deficiency in females: Phenotype\u2010genotype correlation based on a 130\u2010family cohort"],"prefix":"10.1002","volume":"44","author":[{"given":"Stephanie","family":"Gobin\u2010Limballe","sequence":"first","affiliation":[{"name":"Molecular Genetics Department, Necker Hospital APHP Centre\u2010Paris University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Ottolenghi","sequence":"additional","affiliation":[{"name":"Metabolomic and Proteomic Biochemistry Department, 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Institut Imagine Paris University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manel","family":"Guirat","sequence":"additional","affiliation":[{"name":"Molecular Genetics Department, Necker Hospital APHP Centre\u2010Paris University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Rio","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Necker Hospital APHP Centre\u2010Paris University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roselyne","family":"Gesny","sequence":"additional","affiliation":[{"name":"Molecular Genetics Department, Necker Hospital APHP Centre\u2010Paris University  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Gigarel","sequence":"additional","affiliation":[{"name":"Molecular Genetics Department, Necker Hospital APHP Centre\u2010Paris University  Paris 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