Identification of three novel mutations in fourteen patients with citrullinemia type 1

- Three novel variants p.Ala164Pro, p.Leu290Pro and p.Thr389Pro were identified in ASS1 gene.
- Consistent with the literature the pathogenic variant p.Gly390Arg was by far the most common genetic abnormality.
- Initial plasma citrulline levels may allow some inference on the severity of the disease.
- Study underlines the difficulty to always define genotype-phenotype correlation in compound heterozygous pathogenic variants.

ObjectivesCitrullinemia 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.Design & methodsThe 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.ResultsThe mean age of the cohort and the mean age at the time of diagnosis were 48.3 ± 36.5 months (min: 12 days, max: 10 years) and 11.6 ± 26.2 months (min: 3 days, max: 8 years), 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 4 days, 5 days and 2 years, 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.ConclusionIn 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.