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

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.

The functional impact of 1,570 SNP-accessible missense variants in humanOTC

“…It has been suggested that disease presentation in females results from skewed patterns of X-inactivation affecting expression of a wild type and a severe pathogenic SNP. 37–39 We therefore examined the behavior in our assay of amino acid substitutions corresponding to SNPs falling into these three groups (Figure 8).…”

“…It has been suggested that disease presentation in females results from skewed patterns of X-inactivation affecting expression of a wild type and a severe pathogenic SNP. [37][38][39] We therefore examined the behavior in our assay of amino acid substitutions corresponding to SNPs falling into these three groups (Figure 8). The distributions of amino acid substitutions corresponding to neonatal and female variants were very similar and associated with severe loss of activity in our assay (Figure 9).…”

Liver transplantation in ornithine transcarbamylase deficiency: A retrospective multicentre cohort study

“…[ 9 ] Due to the random pattern of X-chromosome inactivation in hepatocytes, approximately 20% of heterozygous females are symptomatic with highly variable age of onset and clinical features. [ 10 ] Acute hyperammonemic decompensations can be precipitated by stressors and become a life-threatening event at any age and any stage of the disease. [ 9 , 11 ]…”

Anesthetic Management of the Surgical Correction of Idiopathic Scoliosis in a Teenager With Ornithine Transcarbamalyse Deficiency

“…Severe deficiencies are more common in males and typically present in the neonatal period, with serious consequences for hyperammonemia and a risk of permanent neurological damage. Partial deficiencies have the greatest possible clinical spectrum and are common in heterozygous females [ 4 ]. In female carriers, severe symptoms in childhood are rare; up to 20% can experience mild symptoms, and some individuals do not experience any symptoms until a stressor, such as pregnancy or delivery, triggers an acute episode of hyperammonemia [ 3 ].…”