Premium
OTC deficiency in females: Phenotype‐genotype correlation based on a 130‐family cohort
Author(s) -
GobinLimballe Stephanie,
Ottolenghi Chris,
Reyal Fabien,
Arnoux JeanBaptiste,
Magen Maryse,
Simon Marie,
Brassier Anaïs,
JabotHanin Fabienne,
Lonlay Pascale De,
Pontoizeau Clement,
Guirat Manel,
Rio Marlene,
Gesny Roselyne,
Gigarel Nadine,
Royer Ghislaine,
Steffann Julie,
Munnich Arnold,
Bonnefont JeanPaul
Publication year - 2021
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1002/jimd.12404
Subject(s) - cohort , genotype , genotype phenotype distinction , genetics , genetic counseling , phenotype , biology , disease , mutation , medicine , odds ratio , gene
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.