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.

中文翻译：

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女性 OTC 缺乏症：基于 130 个家庭队列的表型-基因型相关性

OTC缺乏症是一种固有的尿素循环障碍，是由X连锁OTC基因突变引起的。表型 - 基因型相关性在男性中得到了很好的理解，但在女性中仍然知之甚少。利用 130 个家庭（289 名女性）的队列，我们​​评估了 OTC 酶活性、X 染色体失活和OTC的相对贡献基因测序对杂合子女性的遗传咨询。22% 的杂合女性在临床上受到影响，有发作性 (11%)、慢性 (7.5%) 或新生儿形式的疾病 (3.5%)。总死亡率为4%。OTC 活性，范围从 0% 到 60%，与个体水平的表型无关。对来自 4 个突变肝脏的多个样本的分析显示 OTC 活性和 X 失活曲线的肝内变异性（变异范围：分别为 30% 和 20%）在 4 个肝脏中的 3 个的两个参数之间没有相关性。发现了 90 种致病变异，其中 27 种是新的。基于男性表型和/或计算机预测，突变被分类为“轻度”或“严重”。在我们的队列中，32% 的具有严重突变的女性发生了严重疾病，P  = 1.6e-06)。这些数据应有助于杂合子女性的产前诊断和泛基因组测序中偶然发现 OTC 变异后的遗传咨询。