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. 2021 Sep;44(5):1235-1247.
doi: 10.1002/jimd.12404. Epub 2021 Jun 10.

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

Stephanie Gobin-Limballe  1 , Chris Ottolenghi  2   3 , Fabien Reyal  1   4 , Jean-Baptiste Arnoux  5   6 , Maryse Magen  1 , Marie Simon  1 , Anaïs Brassier  5   6 , Fabienne Jabot-Hanin  7   8 , Pascale De Lonlay  5   6 , Clement Pontoizeau  2   3 , Manel Guirat  1 , Marlene Rio  9 , Roselyne Gesny  1 , Nadine Gigarel  1 , Ghislaine Royer  1 , Julie Steffann  1   3 , Arnold Munnich  3   9 , Jean-Paul Bonnefont  1   3
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OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort

Stephanie Gobin-Limballe et al. J Inherit Metab Dis. 2021 Sep.

Abstract

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.

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

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References

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