4.4 Article

OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort

Journal

JOURNAL OF INHERITED METABOLIC DISEASE
Volume 44, Issue 5, Pages 1235-1247

Publisher

WILEY
DOI: 10.1002/jimd.12404

Keywords

ornithine transcarbamylase; OTC activity; OTC deficiency; phenotype-genotype correlation; X chromosome inactivation

Funding

  1. Assistance Publique -Hopitaux de Paris

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This study on females in OTC deficient families found that 22% of heterozygous females were clinically affected, with a higher risk of severe disease in females with severe mutations. Variability in OTC activity and X inactivation profile within the liver was observed, with little correlation between the two in most cases.
OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X-linked OTC gene. Phenotype-genotype 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 OTC 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-hepatic 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-causing variants were found, 27 of which were novel. Mutations were classified as mild or severe, 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 = 1.365; P = 1.6e-06). These data should help prenatal diagnosis for heterozygous females and genetic counseling after fortuitous findings of OTC variants in pangenomic sequencing.

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