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Case Reports
. 2018 Feb;32(2):e22241.
doi: 10.1002/jcla.22241. Epub 2017 Apr 26.

Carbamoyl phosphate synthetase 1 deficiency diagnosed by whole exome sequencing

Guoqing Zhang  1 , Yulin Chen  2   3 , Huiqun Ju  1 , Fei Bei  1 , Jing Li  1 , Jian Wang  2 , Jianhua Sun  1 , Jun Bu  1
Affiliations
Case Reports

Carbamoyl phosphate synthetase 1 deficiency diagnosed by whole exome sequencing

Guoqing Zhang et al. J Clin Lab Anal. 2018 Feb.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: carbamoyl phosphate synthetase 1 deficiency; gene CPS1; molecular diagnosis; whole exome sequencing.

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Figures

Figure 1
Figure 1
Mutations identified in the gene CPS1 in patient Case 1. Two novel heterozygous missense mutations c.2537C>T (p.Pro846Met) and c.3443T>A (p. Met1148Lys) were identified in Case 1 through exome sequencing. Sanger sequencing showed that the father harbored a heterozygous missense mutation c.2537 C>T (p. Pro846Leu) and the mother had a heterozygous missense mutation c.3443T>A (p.Met1148Lys)
Figure 2
Figure 2
Mutations identified in the gene CPS1 in patient Case 2. A novel heterozygous missense mutations c.1799G>A (p.Cys600Tyr) and a previously reported 12‐bp deletion c.4088_4099del (p.Leu1363_Ile1366del) were detected in the gene CPS1 in Case 2. Sanger sequencing found that the father was heterozygous for the mutation c.4088_4099del (p.Leu1363_Ile1366del) and the mother for the mutation c.1799G>A (p.Cys600Tyr)
Figure 3
Figure 3
Conversation analysis of the substituted amino acids in the CPS1 protein. The amino acid residues at the position of 846 and 1148 of the CPS1 protein in Case 1 were highly conserved. The amino acid residues at the position of 600 and 1363 to 1366 of the CPS1 protein in Case 2 were highly conserved
Figure 4
Figure 4
Homology modeling showed that the mutated amino acids were located in important functional domain. The different domains of the CPS1 protein were labeled by different color in the carton representation. The mutation sites identified in Case 1 were labeled red and pointed out by red arrows. p.Pro846Leu is located in the integrating domain and p.Met1148Lys is located in the carbamate phosphorylation domain
Figure 5
Figure 5
Homology modeling showed that the mutated amino acids were located in important functional domain. The different domains of the CPS1 protein were labeled by different color in the carton representation. The mutation sites identified in Case 2 were labeled red and pointed out by red arrows. p.Cys600Tyr is located in the bicarbonate phosphorylation domain and p.Leu1363_Ile1366del is located in the NAG binding site domain
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