Bai Ruimiao, He ALing, Guo Jinzhen, Li Zhankui, Yu Xiping, Zeng JunAn, Mi Yang, Wang Lin, Zhang Jingjing, Yang Dong
Department of Neonatology, Northwest Women's and Children's Hospital, Xi'an, Shaanxi, China.
Department of Obstetrics, Northwest Women's and Children's Hospital, Xi'an, Shaanxi, China.
Front Neurosci. 2022 Oct 21;16:1025572. doi: 10.3389/fnins.2022.1025572. eCollection 2022.
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonaemia. The biochemical measurement of the intermediate metabolites is helpful for CPS1D diagnosis; it however cannot distinguish CPS1D from N-acetylglutamate synthetase deficiency. Therefore, next-generation sequencing (NGS) is often essential for the accurate diagnosis of CPS1D.
NGS was performed to identify candidate gene variants of CPS1D in a Asian neonatal patient presented with poor feeding, reduced activity, tachypnea, lethargy, and convulsions. The potential pathogenicity of the identified variants was predicted by various types of bioinformatical analyses, including evolution conservation, domain and 3D structure simulations.
Compound heterozygosity of CPS1D were identified. One was in exon 24 with a novel heterozygous missense variant c.2947C > T (p.P983S), and another was previously reported in exon 20 with c.2548C > T (p.R850C). Both variants were predicted to be deleterious. Conservation analysis and structural modeling showed that the two substituted amino acids were highly evolutionarily conserved, resulting in potential decreases of the binding pocket stability and the partial loss of enzyme activity.
In this study, two pathogenic missense variants were identified with NGS, expanding the variants pectrum of the gene. The variants and related structural knowledge of CPS enzyme demonstrate the applicability for the accurate diagnosis of CPS1D.
氨甲酰磷酸合成酶1缺乏症（CPS1D）是一种罕见的常染色体隐性尿素循环障碍，其特征为高氨血症。中间代谢产物的生化检测有助于CPS1D的诊断；然而，它无法将CPS1D与N - 乙酰谷氨酸合成酶缺乏症区分开来。因此，下一代测序（NGS）对于CPS1D的准确诊断通常至关重要。
对一名出现喂养困难、活动减少、呼吸急促、嗜睡和惊厥的亚洲新生儿患者进行NGS，以鉴定CPS1D的候选基因变异。通过各种生物信息学分析预测所鉴定变异的潜在致病性，包括进化保守性、结构域和三维结构模拟。
鉴定出CPS1D的复合杂合性。一个位于外显子24，有一个新的杂合错义变异c.2947C>T（p.P983S），另一个先前在外显子20中报道为c.2548C>T（p.R850C）。两种变异均被预测为有害。保守性分析和结构建模表明，两个取代的氨基酸在进化上高度保守，导致结合口袋稳定性潜在降低和酶活性部分丧失。
在本研究中，通过NGS鉴定出两个致病性错义变异，扩展了该基因的变异谱。CPS酶的变异及相关结构知识证明了其在CPS1D准确诊断中的适用性。
