OBJECTIVE: To explore the genetic basis for a neonate featuring hyperammonemia. METHODS: The patient was examined and tested by tandem mass spectrometry and next generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the proband and her parents. Potential impact of the mutation was predicted with SIFT, PolyPhen-2 and MutationTaste software. RESULTS: Plasma ammonia and alanine were significantly increased in the proband, while serum citrulline was decreased. The neonate was found to harbor compound heterozygous mutations of the CPS1 gene [c.1631C>T(p.T544M) and c.1981G>T(p.G661C)], which were respectively inherited from her father and mother. CONCLUSION The carbamoyl phosphate synthetase I deficiency of the proband can probably be attributed to the mutations of the CPS1 gene. Above finding has expanded the spectrum of CPS1 mutations in association with carbamoyl phosphate synthetase I deficiency.
Carbamoyl-Phosphate Synthase (Ammonia) ; genetics ; Carbamoyl-Phosphate Synthase I Deficiency Disease ; genetics ; Female ; High-Throughput Nucleotide Sequencing ; Humans ; Hyperammonemia ; diagnosis ; genetics ; Infant, Newborn ; Mutation

Diagnosis of the urea cycle disorder (USD) carbamoyl-phosphate synthetase 1 (CPS1) deficiency (CPS1D) based on only the measurements of biochemical intermediary metabolites is not sufficient to properly exclude other UCDs with similar symptoms. We report the first Korean CPS1D patient using whole exome sequencing (WES). A four-day-old female neonate presented with respiratory failure due to severe metabolic encephalopathy with hyperammonemia (1,690 µmol/L; reference range, 11.2-48.2 µmol/L). Plasma amino acid analysis revealed markedly elevated levels of alanine (2,923 µmol/L; reference range, 131-710 µmol/L) and glutamine (5,777 µmol/L; reference range, 376-709 µmol/L), whereas that of citrulline was decreased (2 µmol/L; reference range, 10-45 µmol/L). WES revealed compound heterozygous pathogenic variants in the CPS1 gene: one novel nonsense pathogenic variant of c.580C>T (p.Gln194*) and one known pathogenic frameshift pathogenic variant of c.1547delG (p.Gly516Alafs*5), which was previously reported in Japanese patients with CPS1D. We successfully applied WES to molecularly diagnose the first Korean patient with CPS1D in a clinical setting. This result supports the clinical applicability of WES for cost-effective molecular diagnosis of UCDs.
Base Sequence ; Carbamoyl-Phosphate Synthase (Ammonia)/chemistry/*genetics ; Carbamoyl-Phosphate Synthase I Deficiency Disease/diagnosis/*genetics ; Codon, Nonsense ; Exons ; Female ; Frameshift Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Infant, Newborn ; Republic of Korea ; Sequence Analysis, DNA ; Urea Cycle Disorders, Inborn/diagnosis