title: Identification of three novel mutations in fourteen patients with citrullinemia type 1.
abstract: OBJECTIVE
  Citrullinemia type 1 (CTLN1) is an autosomal recessive genetic disorder caused by mutations in the argininosuccinate synthetase 1 (ASS1) gene, which encodes for the argininosuccinate synthetase enzyme. Here, we report genetic and clinical characterizations of 14 patients with citrullinemia type 1.
  
  
  METHODS
  The study group consisted of 14 patients (4 females, 10 males) diagnosed with citrullinemia type 1 from three centers in Turkey. Age of onset, clinical presentation, initial citrulline and ammonia levels, family history and molecular genetic analysis were retrospectively evaluated.
  
  
  RESULTS
  The mean age of the cohort and the mean age at the time of diagnosis were 48.3±36.5months (min: 12days, max: 10years) and 11.6±26.2months (min: 3days, max: 8years), respectively. In four patients, a homozygous p.Gly390Arg pathogenic variant was detected. All patients homozygous for p.Gly390Arg were diagnosed during the newborn period with the clinical presentation of classical citrullinemia. In each two patients, homozygous p.Arg86His, c.773+49C>T and p.Gly362Val pathogenic variants were detected. Clinical presentation was compatible with the mild form of the disease in patients homozygous for c.773+49C>T and for Gly362Val. Novel compound heterozygous genotypes (p.Ala164Pro/p.Gly390Arg; p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in five patients. Of these, three siblings with CTLN1 were diagnosed with the compound heterozygous genotype p.Ala164Pro/p.Gly390Arg at the age of 4days, 5days and 2years, respectively. The other two patients with novel compound heterozygous genotypes (p.Leu290Pro/p.Gly390Arg; p.Thr389Pro/p.Gly390Arg) were identified in the first month of life as neonatal onset form and were born to non-consanguineous parents.
  
  
  CONCLUSIONS
  In our study, consistent with the literature, a correlation was found between homozygous p.Gly390Arg mutation and the classic neonatal onset form. Mild citrullinemia was detected in patients with c.773+49C>T or p.Gly362Val pathogenic variants. This study adds to our understanding of the molecular genetic background of patients with CTLN1, and allows to infer on the correlation between the genotype and phenotype of the disease.
authors.affiliation: Dokuz Eylul University, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey.
authors.forename: Engin
authors.initials: E
authors.lastname: Kose
authors.affiliation: Ankara Children's Education and Research Hospital, Division of Pediatric Metabolism and Nutrition, Ankara, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Unal
authors.affiliation: Kırıkkale University, Division of Pediatric Metabolism and Nutrition, Kırıkkale, Turkey.
authors.forename: Selda
authors.initials: S
authors.lastname: Bulbul
authors.affiliation: Ankara Children's Education and Research Hospital, Division of Pediatric Metabolism and Nutrition, Ankara, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Gunduz
authors.affiliation: University Children's Hospital Zurich, Division of Metabolism and Children's Research Center, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
authors.affiliation: Dokuz Eylul University, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey; Dokuz Eylul University, Izmir Biomedicine and Genome Center, Izmir, Turkey. Electronic address: nur.arslan@deu.edu.tr.
authors.forename: Nur
authors.initials: N
authors.lastname: Arslan
mesh_terms: D017668:Age of Onset; D000641:Ammonia / Q000097:blood; D001124:Argininosuccinate Synthase / Q000097:blood / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002956:Citrulline / Q000097:blood; D020159:Citrullinemia / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression; D005808:Genes, Recessive; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012189:Retrospective Studies
chemical_list: D002956:Citrulline; D000641:Ammonia; D001124:Argininosuccinate Synthase