Zhang Guoqing, Chen Yulin, Ju Huiqun, Bei Fei, Li Jing, Wang Jian, Sun Jianhua, Bu Jun
Department of Neonatology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Medical Genetics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Clin Lab Anal. 2018 Feb;32(2). doi: 10.1002/jcla.22241. Epub 2017 Apr 26.
Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive inborn metabolic disease characterized mainly by hyperammonemia. The fatal nature of CPS1D and its similar symptoms with other urea cycle disorders (UCDs) make its diagnosis difficult, and the molecular diagnosis is hindered due to the large size of the causative gene CPS1. Therefore, the objective of the present study was to investigate the clinical applicability of exome sequencing in molecular diagnosis of CPS1D in Chinese population.
We described two Chinese neonates presented with unconsciousness and drowsiness due to deepening encephalopathy with hyperammonemia. Whole exome sequencing was performed. Candidate mutations were validated by Sanger sequencing. In-silicon analysis was processed for the pathogenicity predictions of the identified mutations.
Two compound heterozygous mutations in the gene carbamoyl phosphate synthetase 1(CPS1) were identified. One is in Case 1 with two novel missense mutations (c.2537C>T, p. Pro846Leu and c.3443T>A, p.Met1148Lys), and the other one is in Case 2 with a novel missense mutation (c.1799G>A, p.Cys600Tyr) and a previously reported 12-bp deletion (c.4088_4099del, p.Leu 1363_Ile1366del). Bioinformatics deleterious predictions indicated pathogenicity of the missense mutations. Conversation analysis and homology modeling showed that the substituted amino acids were highly evolutionary conserved and necessary for enzyme stability or function.
The present study initially and successfully applied whole exome sequencing to the molecular diagnosis of CPS1D in Chinese neonates, indicating its applicability in cost-effective molecular diagnosis of CPS1D. Three novel pathogenic missense mutations were identified, expanded the mutational spectrum of the CPS1 gene.
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遗传性先天性代谢疾病，主要特征为高氨血症。CPS1D的致命性及其与其他尿素循环障碍（UCDs）相似的症状使得其诊断困难，并且由于致病基因CPS1的基因座较大，分子诊断受到阻碍。因此，本研究的目的是探讨外显子组测序在中国人群CPS1D分子诊断中的临床适用性。
我们描述了两名因高氨血症导致脑病加重而出现昏迷和嗜睡的中国新生儿。进行了全外显子组测序。通过桑格测序验证候选突变。对鉴定出的突变进行了硅内分析以预测其致病性。
在氨甲酰磷酸合成酶1（CPS1）基因中鉴定出两个复合杂合突变。一个在病例1中，有两个新的错义突变（c.2537C>T，p.Pro846Leu和c.3443T>A，p.Met1148Lys），另一个在病例2中，有一个新的错义突变（c.1799G>A，p.Cys600Tyr）和一个先前报道的12bp缺失（c.4088_4099del，p.Leu1363_Ile1366del）。生物信息学有害性预测表明错义突变具有致病性。保守性分析和同源性建模表明，取代的氨基酸具有高度进化保守性，对酶的稳定性或功能至关重要。
本研究首次成功地将全外显子组测序应用于中国新生儿CPS1D的分子诊断，表明其在CPS1D经济有效的分子诊断中的适用性。鉴定出三个新的致病性错义突变，扩大了CPS1基因的突变谱。
