• Test code: 06224
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Arginase Deficiency Test

Test description

The Invitae Arginase Deficiency Test analyzes the ARG1 gene, which is associated with arginase deficiency. This test is useful for the diagnosis of patients in whom arginase deficiency is suspected due to clinical symptoms, biochemical findings, or abnormal newborn screening results. Identification of disease-causing variants can guide treatment and management decisions, and provide accurate risk assessment and carrier status for at-risk relatives.

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Primary panel (1 gene)
  • arginase deficiency

Argininemia, or arginase deficiency, is a rare urea cycle disorder in which deficiency of the arginase enzyme causes the accumulation of the amino acid arginine and ammonia in the blood. Arginase deficiency typically does not present with an acute hepatic encephalopathy that is commonly observed in other urea cycle defects, but has an insidious clinical course with symptoms often not recognized until late infancy or early childhood. Affected, untreated individuals and develop a slowing of linear growth, progressive spastic paraplegia, loss of developmental milestones, intellectual disability, and seizures. Microcephaly has been reported, and cerebral atrophy may be apparent on brain imaging. Clinical severity is variable and some individuals may not develop any signs until later in life.

Unlike other urea cycle disorders, life-threatening episodes of acute hyperammonemia are rare. However, they may occur in infancy or adulthood and are often triggered by other stressors such as illness, infections, periods of fasting or extreme protein load. Symptoms of an acute hyperammonemic episode may include poor feeding, lethargy, respiratory distress, seizures, cerebral edema, vomiting, hypertonia, and hepatomegaly. Untreated episodes can progress to coma and even death.

Patients with arginase deficiency will have elevated arginine on plasma amino acids, elevated orotic acid on urine organic acids and may also have hyperammonemia. The degree of hyperammonemia may not be as severe as other urea cycle defects despite the individual presenting in metabolic crisis.

Treatment options, including restriction of dietary protein and use of oral nitrogen-scavenging drugs, are available for arginase deficiency. Early diagnosis and management may help slow disease progression.

ARG1 is the only gene known to be associated with arginase deficiency. However, due to the rarity of this condition, the percent of arginase deficiency attributed to pathogenic variants in ARG1 is currently unknown.

Arginase deficiency is inherited in an autosomal recessive manner.

The incidence of arginase deficiency has been estimated at 1:950,000.

Any individual with a positive newborn screen for arginase deficiency, deficient activity of the arginase enzyme, elevation of biochemical markers (plasma arginine, urinary orotic acid, plasma ammonia), or a suspected diagnosis of arginase deficiency based on clinical presentation, should be tested. Clinical signs that may indicate testing include loss of developmental milestones, spasticity, seizures and diminished growth. Arginase deficiency is one of the only known treatable causes of spastic paraplegia.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ARG1 NM_000045.3