Identification of rare variants causing urea cycle disorders: A clinical, genetic, and biophysical study

J Cell Mol Med. 2021 Apr;25(8):4099-4109. doi: 10.1111/jcmm.16379. Epub 2021 Feb 21.


Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the congenital deficiency in the eight biomolecules involved in urea cycle. In the present study, five cases of UCD were recruited and submitted to a series of clinical, biochemical, and genetic analysis with a combination of high throughput techniques. Moreover, in silico analysis was conducted on the identified missense genetic variants. Various clinical and biochemical indications (including profiles of amino acids and urinary orotic acids) of UCD were manifested by the five probands. Sequence analysis revealed nine diagnostic variants, including three novel ones, which caused Argininosuccinic aciduria (ASA) in one case, Carbamoyl phosphate synthetase 1deficiency (CPS1D) in two cases, Ornithine transcarbamylase deficiency (OTCD) in one case, and Citrin deficiency in 1case. Results of in silico biophysical analysis strongly suggested the pathogenicity of each the five missense variants and provided insight into their intramolecular impacts. In conclusion, this study expanded the genetic variation spectrum of UCD, gave solid evidence for counselling to the affected families, and should facilitate the functional study on the proteins in urea cycle.

Keywords: argininosuccinic aciduria; carbamoyl phosphate synthetase 1deficiency; citrin deficiency; ornithine transcarbamylase deficiency; urea cycle disorder; whole-exome sequencing.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation*
  • DNA Mutational Analysis
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation, Missense*
  • Ornithine Carbamoyltransferase / genetics*
  • Pedigree
  • Prognosis
  • Urea Cycle Disorders, Inborn / etiology
  • Urea Cycle Disorders, Inborn / metabolism
  • Urea Cycle Disorders, Inborn / pathology*


  • OTC protein, human
  • Ornithine Carbamoyltransferase