Argininemia via the ARG1 Gene

Urea cycle defects are characterized by hyperammonemia, encephalopathy and respiratory alkalosis (Brusilow and Horwich 2014). Eight clinical disorders have been described involving defective urea cycle enzymes or transporter proteins: N-acetylglutamate synthase deficiency, carbamoyl phosphate synthetase I deficiency, ornithine transcarbamolase deficiency, argininosuccinate synthetase deficiency (also known as citrullinemia type I), argininosuccinate lyase deficiency, arginase deficiency, citrin deficiency (also known as citrullinemia type II) and hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome (Ah Mew et al. 2015). Untreated patients with arginase deficiency develop spastic paraplegia, epileptic seizures, and severe mental retardation (Cederbaum et al. 1977; Wong et al. 2014). Hyperammonemia due to arginase deficiency is usually less severe than that arising from defects in the proximal urea cycle enzymes. Early growth and development are generally normal until ages 1 to 3 years when symptoms begin to be evident (Wong et al. 2014). An arginine restricted diet along with sodium benzoate to scavenge ammonia has been found to be effective treatment (Bernar et al. 1986; Wong et al. 2014).

Argininemia is an autosomal recessive disorder caused by pathogenic sequence variants in the ARG1 gene, which is located at chromosome 6q23. ARG1 pathogenic variants are the only known cause of argininemia, and thus far over 50 pathogenic ARG1 sequence variants have been reported in the literature. Missense, nonsense and small deletion variants are the predominant types of disease causing variants in the ARG1 gene, though splice variants, small insertions, duplication and indels, as well as gross deletions, have all been reported (Human Gene Mutation Database).

ARG1 encodes arginase, a liver-specific enzyme that generates urea and ornithine from arginine in the last step of the urea cycle. The ARG1 gene product is also active in red blood cells.

In patients previously diagnosed with elevated serum arginine and decreased enzyme activity, test sensitivity should be very high. For example, in eleven argininemia patients Uchino et al. (1995) detected 21 of 22 possible mutant alleles. Similarly, Cardoso et al. (1999) detected 2 pathogenic alleles in each of 4 patients, and Carvalho et al. (2012) detected 2 pathogenic alleles in each of 16 patients. Overall, this suggests a clinical sensitivity of ~98%.

Overall, large duplications and deletions appear to be relatively rare in the ARG1 gene. To our knowledge, only two large deletions have been reported in the literature to date (Wang et al. 2012; Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ARG1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Note that this test includes coverage for the pathogenic deep intronic variant designated c.306-611T>C.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).