Elevated Arginine/Argininemia via the ARG1 Gene

Newborn screening (NBS) tests are performed soon after birth with the goal of identifying individuals that may be affected by certain disorders before disease-related disability or death occurs. Appropriate medical management beginning early in life can prevent all or many symptoms in the affected individuals (Watson et al. 2006. PubMed ID: 16783161; https://www.cdc.gov/newbornscreening/). While NBS is required within all states and territories in the United States, individual state or territory public health departments determine which conditions are included on the NBS panel (https://www.babysfirsttest.org/newborn-screening/states). NBS protocols outside of the United States vary from country to country. At a minimum, all core conditions on the Recommended Uniform Screening Panel (RUSP) should be included on NBS panels within the United States. In addition, NBS testing may also include secondary conditions, which are disorders that can be detected as part of the differential diagnosis of a core condition (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). Following an abnormal NBS result, follow up diagnostic testing is indicated. Such testing may include biochemical methodologies (for example, urine organic acid analysis or plasma acylcarnitine analysis), enzyme assays, and/or molecular genetic testing.

This test is appropriate for individuals with elevated arginine detected during the NBS process. Elevated arginine can indicate a deficiency of the arginase enzyme. Arginase deficiency is a secondary condition on the RUSP. 

Individuals with arginase deficiency rarely present during the newborn period but can develop mild-to-moderate hyperammonemia once receiving protein in their diet (https://www.acmg.net/PDFLibrary/Arginine.pdf). Untreated individuals may develop features including slowed growth, developmental delay, seizures, and spasticity (Sun et al. 2020. PubMed ID: 20301338; https://www.acmg.net/PDFLibrary/Arginine.pd). Hyperammonemia due to arginase deficiency is usually less severe than that arising from defects in the proximal urea cycle enzymes (Sun et al. 2020. PubMed ID: 20301338). The overall prevalence of arginase deficiency is estimated at between ~1/350,000 and 1/1,000,000 worldwide (Sun et al. 2020. PubMed ID: 20301338). 

Argininemia is an autosomal recessive disorder caused by pathogenic sequence variants in the ARG1 gene. Over 80 pathogenic variants have been reported in the ARG1 gene in the Human Gene Mutation Database (HGMD, https://www.hgmd.cf.ac.uk/; https://www.ncbi.nlm.nih.gov/clinvar/). Missense, nonsense, splicing, and small deletion variants are the predominant types of disease-causing variants in the ARG1 gene, though small insertions, duplications, and indels as well as gross deletions have all been reported in HGMD. 

Several variants have been reported as founder variants or common variants in specific populations: the French Canadian population (c.57+1G>A), the Turkish population (c.61C>T, p.Arg21*), the Brazilian population (c.401C>T, p.Thr134Ile), and the Chinese population (c.703G>A, p.Gly235Arg). To our knowledge, de novo variants in ARG1 have not been reported. 

Pathogenic variants in the ARG1 gene lead to disruption of the arginase enzyme, which is a liver-specific enzyme that generates urea and ornithine from arginine in the last step of the urea cycle. Deficiency of this enzyme results in normal or elevated arginine, elevated glutamine, elevated urinary orotic acid, and possibly elevated ammonia (Sun et al. 2020. PubMed ID: 20301338; http://www.iembase.com/disorder/16).

In patients previously diagnosed with elevated serum arginine and decreased enzyme activity, test sensitivity should be very high. Based on literature reports, clinical sensitivity is expected to be ~90-98% (Uchino et al. 1995. PubMed ID: 7649538; Cardoso et al. 1999. PubMed ID: 10502833; Carvalho et al. 2012. PubMed ID: 22959135). 

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).