• Test code: 06225
  • 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

Invitae Ornithine Transcarbamylase (OTC) Deficiency Test

Test description

The Invitae Ornithine Transcarbamylase (OTC) Deficiency test analyzes the OTC gene which is associated with OTC deficiency. Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants can also aid in determining carrier status and diagnosis of at-risk relatives, including asymptomatic heterozygous females.

Any individual presenting with hyperammonemia, a positive newborn screen for low plasma citrulline, or a suspected diagnosis of OTC based on clinical presentation or laboratory results should be tested for OTC. Age of diagnosis and subsequent metabolic management are some of the greatest determinants of long-term outcome.

Order test

Primary panel (1 gene)
Add-on Hereditary Orotic Aciduria Gene (1 gene)

Hereditary orotic aciduria is a disorder characterized by massive excretions of orotic acid in the urine, megaloblastic anemia, failure to thrive, growth retardation and psychomotor disability, Given the overlap of orotic aciduria with OTC deficiency, it may be appropriate to analyze this gene, particularly in a neonate. This gene can be added at no additional charge.


Add-on Low Citrulline Genes (2 genes)

Carbomylphosphate synthetase (CPS1) deficiency and N-acetylglutamate synthase (NAGS) deficiency are 2 disorders in the urea cycle that can cause low citrulline levels similar to OTC deficiency. However, these disorders do not cause elevations in orotic acid. Given the similarity of low citrulline with all three conditions and ability to test all three genes at the same time instead of sequentially to potentially speed up diagnosis, these genes can be added at no additional charge.


Alternative tests to consider

For a broader analysis of the genetics of urea cycle disorders and organic acidemias:

  • ornithine transcarbamylase (OTC) deficiency
    • affected females (manifesting heterozygotes)

Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect It can present as a severe, neonatal-onset disease in classically affected males, or more moderately, at any point after the neonatal period, in individuals with a partial enzyme deficiency. Carrier females may manifest features similar to classically affected males or remain completely asymptomatic.

Neonatal-onset cases appear healthy at birth, but within a few days of life (following protein ingestion) present with lethargy, vomiting, hypothermia and anorexia. If untreated, their clinical course can deteriorate to include seizures, coma and death. The prognosis of individuals surviving their first hyperammonemic crisis is generally dependent upon the degree of hyperammonemia during the crisis. Neurologic impairment is the most common consequence of hyperammonemic episodes.

Any individual presenting after the neonatal period is considered to have late-onset disease and over half of the cases present after one month of life. There is broad clinical heterogeneity with cases presenting similar to the classic neonatal onset form, or with milder manifestations. Mild cases have even been unmasked following significant protein loads from blood and fluid resorption following crush injury, surgery and childbirth. Milder, adult presentations frequently include a history of chronic headaches, nausea and possible avoidance of high protein foods.

Symptoms in carrier females may range from severe recurrent hyperammonemic episodes to no symptoms at all. The severity of disease is determined by the pattern of X inactivation in the liver, with skewed X-inactivation leading to more significant disease. It is estimated that approximately 15% of heterozygous females will become symptomatic during their lifetime, although this number may be an underestimate due to mild symptoms such as protein self-restriction and headaches not being attributed to OTC deficiency.

Individuals with any form of OTC 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 on plasma amino acids and elevated urine orotic acid.

OTC is the only gene known to cause ornithine transcarbamylase deficiency.

OTC is inherited in an X-linked manner.

The estimated incidence of OTC in the United States is 1:63,000.

This test may be appropriate for any individual with:

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

  1. Batshaw, ML, et al. A longitudinal study of urea cycle disorders. Mol. Genet. Metab. 2014; 113(1-2):127-30. PMID: 25135652
  2. Batshaw, ML, et al. Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency. J. Pediatr. 1986; 108(2):236-41. PMID: 3944708
  3. Msall, M, et al. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N. Engl. J. Med. 1984; 310(23):1500-5. PMID: 6717540
  4. Chiong, MA, et al. Fatal late-onset ornithine transcarbamylase deficiency after coronary artery bypass surgery. Med. J. Aust. 2007; 186(8):418-9. PMID: 17437397
  5. Ben-Ari, Z, et al. Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet. J. Hepatol. 2010; 52(2):292-5. PMID: 20031247
  6. McCullough, BA, et al. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am. J. Med. Genet. 2000; 93(4):313-9. PMID: 10946359
  7. Lichter-Konecki, U, et al. Ornithine Transcarbamylase Deficiency. 2013 Aug 29. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 24006547
  8. Smith, W, et al. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005; 21(4 Suppl):S9-17. PMID: 16227115
  9. Rare Diseases Clinical Research Network. Urea Cycle Disorders Treatment Guidelines.
  10. Brusilow, SW, Maestri, NE. Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr. 1996; 43:127-70. PMID: 8794176

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
CPS1 NM_001875.4
NAGS NM_153006.2
OTC NM_000531.5
UMPS NM_000373.3