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  • Test code: 06123
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Low Citrulline Panel

Test description

Genetic testing for up to four genes that are associated with low citrulline levels on newborn screening (NBS) or plasma amino acid analysis. Low citrulline is an indicator of a proximal urea cycle defect.

Any individual with a positive newborn screen for low citrulline on newborn screening or plasma amino acid analysis, or a suspected diagnosis of a urea cycle defect based on clinical presentation or laboratory results should be tested. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Age of diagnosis and subsequent metabolic management are some of the most important determinants of long-term outcome. Additionally, identification of a disease-causing variant can guide testing and diagnosis of at-risk relatives.

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Primary panel (3 genes)
Add-on Limited Evidence Gene (1 gene)

Patients with ALDH18A1-related conditions, particularly pyrroline-5-carboxylate synthetase (P5CS) deficiency, can have low citrulline, similar to patients with OTC deficiency, NAGS deficiency, or CPS1 deficiency; despite having additional biochemical abnormalities that distinguish these disorders. Patients with ALDH18A1-related conditions can have hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia, and hypoprolinemia. Given the biochemical overlap between ALDH18A1-related conditions and other disorders that may cause low citrulline, analyzing the ALDH18A1 gene may be appropriate. This gene can be included at no additional charge

ALDH18A1

Alternative tests to consider

For a broader analysis of the genetics of urea cycle disorders:

  • carbamoyl phosphate synthetase 1 (CPS1) deficiency
  • N-acetylglutamate synthase (NAGS) deficiency
  • ornithine transcarbamylase (OTC) deficiency

Proximal urea cycle defects have similar clinical presentations that are primarily characterized by encephalopathy secondary to hyperammonemia. Symptoms may appear at any time from the neonatal period through adulthood, and anything occurring after the immediate neonatal period is considered late-onset. Neonatal-onset cases appear healthy at birth, but within a few days of life present with lethargy, vomiting, hypothermia and anorexia. Late-onset cases have a similar clinical presentation but the manifestations can be less severe. Adult presentations frequently include a history of chronic headaches and nausea. If untreated, proximal urea cycle defects can progress to coma and death, or lead to severe neurologic impairments. All urea cycle defects frequently present with recurrent hyperammonemic episodes that are often precipitated by protein ingestion, illness or other physiologic stress. Treatment for urea cycle defects is available through dietary protein restriction, nitrogen scavenging drugs and/or liver transplant. Biochemical findings include hyperammonemia, low (or absent) plasma citrulline and high plasma glutamine. CPS1 and NAGS deficiencies have low urine orotic acid, whereas OTC deficiency has elevated urine orotic acid.

CPS1 deficiency
Carbamoyl phosphate synthetase 1 (CPS1) is the entry point for the urea cycle. It is involved in the condensation of ammonium ions and carbon dioxide to form carbamoyl phosphate.

NAGS deficiency
N-acetylglutamate (NAG) is a cofactor for the enzyme CPS1. NAG is synthesized by the enzyme NAG synthase (NAGS) from glutamate and acetylCoA. NAGS deficiency results in inadequate NAG cofactor production, impaired CPS1 enzyme and inhibition of the urea cycle.

Ornithine transcarbamylase (OTC) deficiency
Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect and is the second step of the urea cycle. OTC is involved in the condensation of carbamoyl phosphate and ornithine to form citrulline.

Gene attribution for proximal urea cycle defects

Gene % Gene Attribution
CPS1 5%
NAGS rare
OTC 59%

CPS1 and NAGS deficiencies are inherited in an autosomal recessive manner. OTC is an X-linked condition.

The estimated incidence of the proximal urea cycle defects are:

  • CPS1 – 1:1,300,000
  • NAGS – 1:2,000,000
  • OTC – 1:56,500

This panel may be appropriate for any individual with:

  • a low citrulline level on plasma amino acid analysis
  • a low citrulline level on newborn screening
  • a low citrulline level and hyperammonemia

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, +/- 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
ALDH18A1 NM_002860.3
CPS1 NM_001875.4
NAGS NM_153006.2
OTC* NM_000531.5

OTC: Analysis includes the intronic variant NM_000531.5:c.540+265G>A.