OTC deficiency in females: Phenotype-genotype correlation based on a 130-family cohort
| Autor: | Nadine Gigarel, Fabien Reyal, Pascale de Lonlay, Ghislaine Royer, Chris Ottolenghi, Clément Pontoizeau, Jean-Paul Bonnefont, Arnold Munnich, Manel Guirat, Julie Steffann, Fabienne Jabot-Hanin, Stephanie Gobin-Limballe, Anaïs Brassier, Marlène Rio, Marie Simon, Jean-Baptiste Arnoux, Maryse Magen, Roselyne Gesny |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Heterozygote Urea cycle disorder Genetic counseling Ornithine transcarbamylase Physiology Prenatal diagnosis X-inactivation 03 medical and health sciences Genetics Medicine Humans Family Genetics (clinical) Genetic Association Studies Ornithine Carbamoyltransferase 030304 developmental biology 0303 health sciences business.industry Mortality rate 030305 genetics & heredity Odds ratio medicine.disease Ornithine Carbamoyltransferase Deficiency Disease Liver Cohort Mutation Female business |
| Zdroj: | Journal of inherited metabolic diseaseREFERENCES. 44(5) |
| ISSN: | 1573-2665 |
| Popis: | 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 counselling 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. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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