The Invitae Elevated Arginine Test analyzes ARG1, the gene that is associated with elevated arginine on newborn screening (NBS) or plasma amino acids. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives.
The Invitae Urea Cycle Disorders Panel has been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.
ARG1 encodes arginase, the enzyme that catalyzes the cleavage of arginine to urea and ornithine—the last step of the urea cycle. Arginase deficiency is a urea-cycle disorder, and the accumulation of arginine is the biochemical hallmark of this condition. Unlike other urea-cycle disorders, arginase deficiency is not generally associated with a severe hyperammonemic encephalopathy in the neonatal period because severe hyperammonemia rarely occurs in this condition. Instead, arginase deficiency typically presents later in childhood, between two and four years of age, with predominantly neurological features. Clumsiness, failure to thrive, and short stature may be observed in early childhood; psychomotor deterioration may be seen from three months to four years of age. The disease is slowly progressive relative to other urea-cycle disorders; nevertheless, if it remains untreated, it advances with developmental regression and spasticity.
It is important to note that arginase deficiency is one of the few treatable causes of spastic diplegia.
For patients with symptoms that are consistent with arginase deficiency and a biochemical diagnosis of arginase deficiency, more than 95% will have two pathogenic mutations in the ARG1 gene.
Arginase deficiency is inherited in an autosomal recessive manner.
The estimated incidence of arginase deficiency is 1 in 950,000 newborn screens. It affects 3 in 7,000 institutionalized individuals with mental retardation.
For considerations for testing please refer to:
For management guidelines please refer to:
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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
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|