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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Family
  • Female
  • Genetic Association Studies
  • Heterozygote
  • Humans
  • Liver / enzymology
  • Male
  • Mutation*
  • Ornithine Carbamoyltransferase / genetics*
  • Ornithine Carbamoyltransferase Deficiency Disease / mortality*


  • Ornithine Carbamoyltransferase