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Invitae Hyperammonemia Panel

Test description

The Invitae Hyperammonemia Panel analyzes genes that are associated with the enzymes and transporter proteins responsible for the production and detoxification of ammonia, the waste product of protein metabolism. Deficiency of any of these proteins may result in an excess of ammonia in the blood, hyperammonemia. If this condition is untreated it can cause severe brain damage and death. The genes in this panel were selected based on the available evidence to date and represent Invitae’s broadest test for disorders associated with hyperammonemia.

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Primary panel (58 genes)

ABCD4 ACADM ACADVL ALDH18A1 ARG1 ASL ASS1 BCKDHA BCKDHB BTD CA5A CPS1 CPT1A CPT2 DBT DLAT DLD ETFA ETFB ETFDH GLUD1 GLUL HADHA HADHB HCFC1 HLCS HMGCL IVD LMBRD1 MCCC1 MCCC2 MCEE MMAA MMAB MMACHC MMADHC MTR MTRR MUT NAGS OAT OTC PC PCCA PCCB PDHA1 PDHB PDHX PDP1 SERAC1 SLC22A5 SLC25A13 SLC25A15 SLC25A20 SLC7A7 TAZ TMEM70 UMPS

Branched-chain organic acidurias

  • 3-methylcrotonyl-CoA carboxylase
  • 3-hydroxy-3-methylglutaryl (3HMG)-CoA lyase deficiency
  • isovaleric acidemia
  • maple syrup urine disease, classic
  • maple syrup urine disease, intermediate
  • maple syrup urine disease, intermittent
  • maple syrup urine disease, thiamine-responsive
  • methylmalonyl-CoA epimerase deficiency
  • methylmalonyl-CoA mutase
  • propionic acidemia

Biotin responsive
  • biotinidase deficiency
  • holocarboxylase synthetase deficiency

Disorders of cobalamin (vitamin B12) metabolism
  • cobalamin A type methylmalonic aciduria
  • cobalamin B type methylmalonic aciduria
  • cobalamin D (cblD) deficiency
  • cobalamin G (cblG) deficiency
  • homocystinuria due to cobalamin E deficiency
  • methylmalonic aciduria and homocystinuria type cblC
  • methylmalonic aciduria and homocystinuria, cblF type
  • methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency
  • methylmalonic aciduria with homocystinuria due to cobalamin J (cblJ) deficiency
  • methylmalonic acidemia and homocysteinemia, cblX

Fatty acid oxidation
  • carnitine palmitoyltransferase deficiency I
  • carnitine palmitoyltransferase deficiency II
  • carnitine-acylcarnitine translocase deficiency
  • long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)
  • medium-chain acyl-CoA dehydrogenase deficiency
  • mitochondrial trifunctional protein deficiency
  • multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia IIA)
  • multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia IIB)
  • multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia IIC)
  • primary carnitine deficiency
  • trifunctional protein deficiency
  • very long-chain acyl-CoA dehydrogenase deficiency

Pyrimidine metabolism (orotic aciduria differential)
  • orotic aciduria

Pyruvate and TCA cycle
  • dihydrolipoamide dehydrogenase deficiency
  • pyruvate carboxylase deficiency
  • pyruvate dehydrogenase E1-alpha deficiency
  • pyruvate dehydrogenase E1-beta deficiency
  • pyruvate dehydrogenase E2 deficiency
  • pyruvate dehydrogenase E3-binding protein deficiency
  • pyruvate dehydrogenase phosphatase deficiency

Respiratory chain defects, mitochondrial disorders, and phospholipid disorders causing methylmalonic aciduria or 3-methylglutaconic aciduria
  • 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL)
  • ATP synthase deficiency; Mitochondrial Complex V Deficiency Nuclear Type 2 (MC5DN2)
  • Barth syndrome; 3-methylglutaconic aciduria type II and dilated cardiomyopathy

Urea Cycle
  • arginase deficiency
  • argininosuccinate lyase deficiency
  • argininosuccinate synthetase deficiency
  • carbamoyl phosphate synthetase I deficiency
  • citrin deficiency
  • citrullinemia type I
  • congenital glutamine deficiency
  • delta-1-pyrroline-5-carboxylate synthase deficiency (P5CS)
  • gyrate atrophy of choroid and retina
  • hyperammonemia due to carbonic anhydrase VA deficiency (CA5AD)
  • familial hyperinsulinism-hyperammonemia syndrome
  • hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
  • lysinuric protein intolerance
  • N-acetylglutamate synthase deficiency
  • ornithine transcarbamylase deficiency
  • ornithine-delta-aminotransferase deficiency

The urea cycle is the principal biochemical pathway for ammonia detoxification. Therefore, defects in the function of any component of the urea cycle are the primary cause of hyperammonemia. The clinical manifestations of urea cycle disorders are highly variable dependent on the severity of specific deficiencies. Significant or total loss of 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. Patients with marginal functioning enzymes encoded by ARG1, ASL, ASS1, CPS1, OTC or SLC25A13 usually do not experience hyperammonemia until a catabolic inducing event such as illness or excessive stress occurs. In these instances, the clinical presentation is often lessened, with no initial clinical indication for months or even decades. Ancillary causes of hyperammonemia include deficiency of genes that lead to the indirect inhibition of the urea cycle by two means: production of inhibitors or reduction of essential substrates. This includes genes encoding proteins involved in such metabolic pathways as branch chain amino acid metabolism (organic acidurias) and fatty acid oxidation.

The progression of the clinical consequences of hyperammonemia may continue despite therapeutic intervention, even when administered in the initial stages of a given disorder. Further, hepatic dysfunction as a result of pharmacological side effects, viral infection and vascular bypass of the liver, can result in hyperammonemia and resemble the effects of a genetic disorder. The Invitae Urea Cycle Disorders Panel can help differentiate the underlying primary defect and cause of hyperammonemia and guide appropriate treatment.

This panel covers the vast majority of genetic conditions that can cause hyperammonemia. The following table provides estimated gene attribution for primary hyperammonemia caused by 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 metabolic conditions are inherited in an autosomal recessive manner. Ornithine transcarbamylase (OTC) deficiency, congenital glutamine deficiency, cobalamin X deficiency, pyruvate dehydrogenase E1-alpha deficiency are inherited in an X-linked manner.

For urea cycle defects resulting in primary hyperammonemia, the estimated incidence is 1 in 8,500 to 1 in 35,000 live births. Overall incidence of hyperammonemia is unknown due to the high variability of the different associated disorders. It is also likely to be underestimated due to a significant proportion of undetected affected and asymptomatic patients (PMID: 25735860).

This test may be appropriate for patients with a plasma ammonia concentration of 150 μmol/L or higher associated with a normal anion gap and a normal plasma glucose concentration.

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
ABCD4 NM_005050.3
ACADM NM_000016.5
ACADVL NM_000018.3
ALDH18A1 NM_002860.3
ARG1 NM_000045.3
ASL NM_000048.3
ASS1 NM_000050.4
BCKDHA NM_000709.3
BCKDHB NM_183050.2
BTD NM_000060.3
CA5A NM_001739.1
CPS1 NM_001875.4
CPT1A NM_001876.3
CPT2 NM_000098.2
DBT NM_001918.3
DLAT NM_001931.4
DLD NM_000108.4
ETFA NM_000126.3
ETFB NM_001985.2
ETFDH NM_004453.3
GLUD1 NM_005271.4
GLUL NM_002065.6
HADHA NM_000182.4
HADHB NM_000183.2
HCFC1 NM_005334.2
HLCS NM_000411.6
HMGCL NM_000191.2
IVD NM_002225.3
LMBRD1 NM_018368.3
MCCC1 NM_020166.4
MCCC2 NM_022132.4
MCEE NM_032601.3
MMAA NM_172250.2
MMAB NM_052845.3
MMACHC NM_015506.2
MMADHC NM_015702.2
MTR NM_000254.2
MTRR* NM_002454.2
MUT NM_000255.3
NAGS NM_153006.2
OAT NM_000274.3
OTC* NM_000531.5
PC* NM_000920.3
PCCA NM_000282.3
PCCB NM_000532.4
PDHA1 NM_000284.3
PDHB NM_000925.3
PDHX NM_003477.2
PDP1 NM_018444.3
SERAC1 NM_032861.3
SLC22A5 NM_003060.3
SLC25A13 NM_014251.2
SLC25A15 NM_014252.3
SLC25A20 NM_000387.5
SLC7A7 NM_001126106.2
TAZ NM_000116.4
TMEM70 NM_017866.5
UMPS NM_000373.3

MTRR: Analysis includes the intronic variant NM_002454.2:c.903+469T>C.
OTC: Analysis includes the intronic variant NM_000531.5:c.540+265G>A.
PC: Analysis includes the intronic variant NM_000920.3:c.1369-29A>G.