Pathogenic variants in non-coding regions of genes encoding enzymes or transporters of the urea cycle can lead to urea cycle disorders (UCDs). However, not all commercially available testing platforms interrogate these regions. Here, we used a gene panel based on massively parallel sequencing (MPS) in 10 individuals with clinical or pedigree-based evidence of a proximal UCD but without a molecular confirmation of the diagnosis. We identified causal variant(s) in 5 of 10 individuals, including in 3 of 7 individuals in whom prior molecular testing was unrevealing. We show that a deep-intronic pathogenic variant in OTC, c.540+265G>A, is an important cause of ornithine transcarbamylase (OTC) deficiency.

编码尿素循环酶或转运蛋白的基因非编码区的致病性变异可导致尿素循环障碍（UCD）。但是，并非所有的商用测试平台都会询问这些区域。在这里，我们使用了基于大规模并行测序（MPS）的基因组，对10名具有近端UCD的临床或基于血统的证据进行了诊断，但没有分子确诊的证据。我们在10个个体中的5个中确定了因果变异，其中7个个体中有3个以前的分子测试无法揭示。我们显示，在OTC中，c.540 + 265G> A是一种深度内含子致病变异，是鸟氨酸转氨甲酰酶（OTC）缺乏的重要原因。