Invitae Urea Cycle Disorders Panel

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  • Test code: 06212
  • 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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Test description

The Invitae Urea Cycle Disorders Panel analyzes up to 15 genes encoding the enzymes and transporter proteins involved in the urea cycle. The urea cycle is a biochemical pathway responsible for the detoxification of ammonia, the waste product of protein metabolism. Partial or complete deficiency in the function of the affected enzyme or transporter results in hyperammonemia, which, if untreated, can cause severe brain damage and death. The genes in this panel were selected based on the available evidence to date to provide Invitae’s broadest test for urea cycle disorders.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provide accurate recurrence risk assessment and carrier status in at risk relatives.

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Primary panel (10 genes)

ALDH18A1 ARG1 ASL ASS1 CPS1 NAGS OAT OTC SLC25A13 SLC25A15

Add-on Hyperammonemia Genes (4 genes)

Pathogenic variants in these genes can also cause hyperammonemia; carbonic anhydrase deficiency (CA5A), glutamate dehydrogenase deficiency (GLUD1), glutamine synthetase deficiency (GLUL), and lysinuric protein intolerance (SLC7A7). These genes can be added at no extra charge.

CA5A GLUD1 GLUL SLC7A7

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 some conditions of the urea cycle, it may be appropriate to analyze this gene, particularly in a neonate. This gene can be added at no additional charge.

UMPS

Alternative tests to consider

The Invitae Organic Acidemias Panel and the Invitae Fatty Acid Oxidation Defects Panel have been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. They can be ordered at no additional cost.

  • urea cycle disorders
    • ALDH18A1-related cutis laxa
    • ALDH18A1-related spastic paraplegia
    • arginase (ARG1) deficiency
    • argininosuccinate lyase (ASL) deficiency
    • carbamoyl phosphate synthetase I (CPSI) deficiency
    • citrin deficiency
    • citrullinemia type I
    • citrullinemia type II
    • gyrate atrophy (OAT)
    • HMG-CoA lyase (HMGCL) deficiency
    • hyperammonemia-hyperornithinemia-homocitrullinuria (HHH) syndrome
    • N-acetylglutamate synthase (NAGS) deficiency
    • ornithine aminotransferase (OAT) deficiency
    • ornithine transcarbamylase (OTC) deficiency

The urea cycle disorders are a group of inherited metabolic diseases that cause hyperammonemia and abnormal amino acid metabolism Typically, they are caused by a deficiency of one of the enzymes or transporter proteins that participate in the urea cycle. These reactions are required for the detoxification of ammonia—the waste product of protein metabolism. In patients with urea cycle disorders, the waste-removal function of the liver is impaired, causing the accumulation of ammonia in the blood, which, at a high level, can cause brain damage, coma, and death. Symptoms of urea cycle disorders are relatively nonspecific; the severity depends on the gene that has been disrupted as well as on the extent of the functional deficiency of the resulting enzyme or transporter. Infants with severe deficiency or total absence of the urea cycle enzymes encoded by ASL, ASS1, CPS1, OTC or the cofactor producer encoded by NAGS are typically normal at birth but develop severe symptoms in the first few days of life, including cerebral edema, lethargy, irritability, anorexia, vomiting, hyper- or hypoventilation, hypothermia, seizures, and neurologic posturing. If left untreated, the symptoms become progressively worse and cause hypotonia, coma, and death. In partial deficiencies of enzymes encoded by ARG1, ASL, ASS1, CPS1, or OTC, or in the mitochondrial aspartate-glutamate transporter defect (citrin encoded by SLC25A13), patients may do well until ammonia accumulation is triggered by stress or another illness, causing the body to enter a state of increased protein catabolism. In the case of a partial deficiency, the symptoms and elevated concentrations of ammonia in the plasma are often subtle, with the first recognized clinical episode not occurring for months or even decades.

The ALDH18A1 gene encodes the enzyme delta1-pyrroline-5-carboxylate synthase (P5C synthase), which catalyzes the reduction of glutamate to P5C—a critical step in the de novo biosynthesis of proline, ornithine, and arginine. Enzymatic deficiency caused by disruption of the ADH18A1 gene leads to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia, and hypoprolinemia and may be associated with neurodegeneration, cataracts, and connective tissue diseases, including ALDH18A1-related cutis laxa and ALDH18A1-related spastic paraplegia.

The OAT gene encodes the enzyme ornithine aminotransferase. Deficiency of this enzyme impedes the conversion of ornithine into P5C and causes gyrate atrophy of the choroid and retina. This disease is characterized by progressive vision loss. Patients suffer from ongoing atrophy of the retina and nearby choroid tissue. Beginning from childhood, patients experience myopia, night blindness, and loss of peripheral vision. These progressive vision changes lead to blindness by age 50. Many people with gyrate atrophy also develop cataracts. Most people with gyrate atrophy have no symptoms other than vision loss. Occasionally, newborns with gyrate atrophy develop hyperammonemia, which may lead to feeding problems, vomiting, seizures, or coma. Neonatal hyperammonemia associated with gyrate atrophy generally responds quickly to treatment and does not recur after the newborn period.

The SLC25A15 gene encodes the mitochondrial ornithine transporter 1 (ORNT1), which is involved in the urea cycle and the ornithine degradation pathway. The metabolic triad of persistent hyperornithinemia, episodic or postprandial hyperammonemia, and urinary excretion of homocitrulline establishes the diagnosis of hyperornithinemia-hyperammonemia- homocitrullinuria (HHH) syndrome. The neonatal form is seen in approximately 12% of diagnosed patients. Infants have no symptoms for the first 24–48 hours, followed by an onset of hyperammonemia-related symptoms. The majority of patients (>80%) have later onset, with presentations during infancy, childhood, or even adulthood. Affected individuals may present chronic neurocognitive deficits and liver dysfunction, as well as acute encephalopathy that is secondary to hyperammonemic crisis and may have been precipitated by a variety of factors.

Neurologic findings and cognitive abilities that are related to urea-cycle disorders can continue to deteriorate despite early metabolic control preventing hyperammonemia. Further, disorders that perturb the liver, such as viral infection and vascular bypass of the liver, can result in hyperammonemia and resemble the effects of a urea cycle disorder.

In urea-cycle disorders, hyperammonemia is the primary metabolic abnormality caused by a urea cycle enzyme or transport deficiency. Secondary hyperammonemia can be caused by other metabolic defects, such as organic acid disorders and fatty acid oxidation disorders, drugs, other metabolites that may interfere with urea cycle function, and severe liver disease. The Invitae Urea Cycle Disorders Panel can help differentiate the underlying primary defect and cause of hyperammonemia and guide appropriate treatment.

The most common urea-cycle defect is OTC deficiency followed by ASL deficiency and ASS deficiency. The following table provides estimated gene attribution for urea-cycle disorders (PMID: 23972786).

Gene Gene attribution
ALDH18A1 Rare
ARG1 3%
ASL 16%
ASS1 14%
CPS1 5%
NAGS Rare
OAT Rare
OTC 59%
SLC25A13 <1%
SLC25A15 1%

The majority of urea-cycle disorders are inherited in an autosomal recessive fashion. Exceptions include ALDH18A1-related cutis laxa and ADH18A1-related spastic paraplegia, which can be inherited in autosomal dominant or recessive modes, and X-linked ornithine transcarbamylase deficiency.

Incidence ranges from 1 in 8,500 to 1 in 35,000 live births. The exact incidence of these disorders is unknown; it is likely underestimated because the clinical symptoms of urea-cycle disorders are nonspecific, and many affected individuals remain undiagnosed. Affected infants may die due to a urea cycle disorder before a definitive diagnosis can be made.

A plasma ammonia concentration of 150 μmol/L or higher associated with a normal anion gap and a normal plasma glucose concentration is a strong indication of a urea-cycle disorder.

  1. Ah, Mew, N, et al. Urea Cycle Disorders Overview. 2003 Apr 29. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301396
  2. Batshaw, ML, et al. A longitudinal study of urea cycle disorders. Mol. Genet. Metab. 2014; 113(1-2):127-30. PMID: 25135652
  3. Camacho, J, Rioseco-Camacho, N. Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome. 2012 May 31. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 22649802
  4. Coutelier, M, et al. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain. 2015; 138(Pt 8):2191-205. PMID: 26026163
  5. Heidelberg: Springer; 2012. Chapter 20, Disorders of the urea cycle and related enzymes; p. 297–310.
  6. Lee, B, Goss, J. Long-term correction of urea cycle disorders. J. Pediatr. 2001; 138(1 Suppl):S62-71. PMID: 11148551
  7. Mohamed, M, et al. Metabolic cutis laxa syndromes. J. Inherit. Metab. Dis. 2011; 34(4):907-16. PMID: 21431621
  8. New England Consortium of Metabolic Programs. Neonate/Infant/Child with Hyperammonemia. http://newenglandconsortium.org/for-professionals/acute-illness-protocols/urea-cycle-disorders/neonate-infant-child-with-hyperammonemia/ Accessed February 2016.
  9. Summar, M, Tuchman, M. Proceedings of a consensus conference for the management of patients with urea cycle disorders. J. Pediatr. 2001; 138(1 Suppl):S6-10. PMID: 11148544
  10. Summar, M. Current strategies for the management of neonatal urea cycle disorders. J. Pediatr. 2001; 138(1 Suppl):S30-9. PMID: 11148547
  11. Summar, ML, et al. The incidence of urea cycle disorders. Mol. Genet. Metab. 2013; 110(1-2):179-80. PMID: 23972786
  12. Waisbren, SE, et al. Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. J. Inherit. Metab. Dis. 2016; 39(4):573-84. PMID: 27215558
  13. Wijburg FA, Nassogne MC. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 20, Disorders of the Urea Cycle and Related Enzymes; p. 297–310.

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALDH18A1 NM_002860.3
ARG1 NM_000045.3
ASL NM_000048.3
ASS1 NM_000050.4
CA5A NM_001739.1
CPS1 NM_001875.4
GLUD1 NM_005271.4
GLUL NM_002065.6
NAGS NM_153006.2
OAT NM_000274.3
OTC* NM_000531.5
SLC25A13 NM_014251.2
SLC25A15 NM_014252.3
SLC7A7 NM_001126106.2
UMPS NM_000373.3

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