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Invitae Urea Cycle Disorders Panel

Test code: 06212

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.

Disorders tested

Ordering information

Turnaround time:

10–21 calendar days (14 days on average)

New York approved:

Yes

Preferred specimen:

3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)

Alternate specimens:

Saliva, buccal swab, and gDNA are also accepted.
Learn more about specimen requirementsRequest a specimen collection kit

Clinical description and sensitivity

Clinical description:

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.

Clinical description and sensitivity

Assay 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, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. 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.

Assay information

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You can customize this test by clicking genes to remove them.

Primary panel

10 genes selected
ALDH18A1
ARG1
ASL
ASS1
CPS1
NAGS
OAT
OTC
SLC25A13
SLC25A15
Select add-on 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.

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.

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