Hyperammonemia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10407 ABCD4 81479,81479 Order Options and Pricing
ACADM 81479,81479
ACADS 81405,81479
ACADVL 81406,81479
ACAT1 81479,81479
ALDH18A1 81479,81479
ARG1 81479,81479
ASL 81479,81479
ASS1 81406,81479
BCKDHA 81405,81479
BCKDHB 81406,81479
BTD 81404,81479
CA5A 81479,81479
CAD 81479,81479
CPS1 81479,81479
CPT1A 81479,81479
CPT2 81404,81479
DBT 81406,81405
DLD 81406,81479
ETFA 81479,81479
ETFB 81479,81479
ETFDH 81479,81479
FBXL4 81479,81479
GLUD1 81406,81479
GLUL 81479,81479
HADH 81479,81479
HADHA 81406,81479
HADHB 81406,81479
HCFC1 81479,81479
HLCS 81406,81479
HMGCL 81479,81479
HMGCS2 81479,81479
IVD 81406,81479
LMBRD1 81479,81479
MCCC1 81406,81479
MCCC2 81406,81479
MLYCD 81479,81479
MMAA 81405,81479
MMAB 81405,81479
MMACHC 81404,81479
MMADHC 81479,81479
MMUT 81406,81479
MRPS22 81479,81479
MTR 81479,81479
MTRR 81479,81479
NAGS 81479,81479
NBAS 81479,81479
OAT 81479,81479
OTC 81405,81479
PC 81406,81479
PCCA 81406,81405
PCCB 81406,81479
SERAC1 81479,81479
SLC22A5 81405,81479
SLC25A13 81479,81479
SLC25A15 81479,81479
SLC25A20 81405,81404
SLC25A42 81479,81479
SLC7A7 81479,81479
TANGO2 81479,81479
TAZ 81406,81479
TMEM70 81479,81479
UQCRC2 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10407Genes x (63)81479 81404, 81405, 81406, 81479 $1030 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Hyperammonemia is the occurrence of elevated levels of ammonia in the plasma. Normal ammonia levels are considered to be <110 μmol/L (190 μg/dL) in newborns and <80 μmol/L (140 μg/dL) in older infants and adults (Nyhan et al. 2017). Ammonia is toxic to the brain and is typically removed quickly from circulation via the urea cycle (Rabier. 2016). When this does not occur properly and ammonia levels increase substantially above these cutoffs, a number of clinical symptoms can occur. These include rapid, acute encephalopathy, decreased consciousness, psychiatric symptoms (such as personality changes, agitated and aggressive behavior, and decreased cognition), vomiting, abnormal gait and/or posturing, and seizures (LaBuzetta et al. 2010. PubMed ID: 20920686; Rabier 2016). Hyperammonemia can lead to irreversible brain damage, coma and death if not identified and treated rapidly, and is considered a medical emergency (LaBuzetta et al. 2010. PubMed ID: 20920686; Lachmann and Murphy. 2016; Ali et al. 2020. PubMed ID: 32491436).

The various conditions that cause hyperammonemia can be classified as either primary or secondary hyperammonemias. Primary hyperammonemia is due to a dysfunction of the urea cycle that leads directly to the build-up of ammonia. Classical urea cycle defects are caused by pathogenic variants in the ARG1, ASL, ASS1, CPS1, NAGS or OTC genes. These genes all encode proteins that play direct roles in the urea cycle, and are only active in the liver (Häberle. 2013. PubMed ID: 23628343).

Secondary hyperammonemias occur when the urea cycle is inhibited due to substrate deficiencies or the accumulation of metabolites that inhibit the action of one or more of the urea cycle enzymes (Häberle. 2013. PubMed ID: 23628343). In addition, as the urea cycle operates only in the liver, factors that affect liver function can also disrupt the urea cycle and lead to hyperammonemia (Häberle. 2013. PubMed ID: 23628343; Monch. 2015; Rabier. 2016). Genetic causes of secondary hyperammonemias can include the organic acidemias (primarily methylmalonic acidemia, propionic acidemia, and isovaleric acidemia), lysinuric protein intolerance, pyrroline-5-carboxylate synthetase deficiency, glutamine synthase deficiency, disorders that cause a decrease in the availability of acetyl-CoA (such as fatty acid oxidation defects), and defects in the carnitine cycle (Häberle. 2013. PubMed ID: 23628343).

Three of the genes in this panel (HCFC1, associated with methylmalonic acidemia and homocysteinemia, cblX type; OTC, associated with ornithine transcarbamylase deficiency; and TAZ, associated with Barth syndrome) are inherited in an X-linked manner. Female carriers of HCFC1 pathogenic variants are generally unaffected (Sloan et al. 2018. PubMed ID: 20301503), whereas females carriers of pathogenic OTC variants can experience serious symptoms early in life or in adulthood (Lichter-Konecki et al. 2016. PubMed ID: 24006547). Female carriers of pathogenic TAZ variants are typically unaffected, although in rare cases females with other X chromosome abnormalities (such as 45,X, structural abnormalities of the X chromosome, or skewed X-inactivation) may be symptomatic (Ferreira et al. 2020. PubMed ID: 25299040; Sabbah. 2020. PubMed ID: 33001359).   

Although it is difficult to estimate the overall prevalence of the various genetic causes of hyperammonemia, the estimated incidence of urea cycle disorders is ~1/250,000 live births in the United States, and ~1/440,000 live births internationally (Ali et al. 2020. PubMed ID: 32491436). The most common genetic cause of primary hyperammonemia in adults has been reported to be OTC deficiency in symptomatic, heterozygous female carriers (Rabier. 2016).

Additional, non-genetic causes of hyperammonemia can include transient hyperammonemia of the newborn, infection (particularly urinary tract infections caused by urease-producing bacteria), alcohol and/or drug misuse, hepatic disease, increased protein load, cancer and chemotherapy, and vascular shunts (Häberle. 2013. PubMed ID: 23628343; Monch. 2015; Rabier. 2016; Ali et al. 2020. PubMed ID: 32491436).

Molecular testing is useful to confirm a genetic cause of a hyperammonemic episode, which may then be useful for determining appropriate treatment and management measures, assessment of recurrence risks, and may allow for appropriate screening for potential future symptoms. Testing may also be useful for at-rick family members and reproductive planning.

Genetics

This sequencing panel currently includes genes that have been associated with primary or secondary hyperammonemia. The majority of the disorders associated with these genes are inherited in an autosomal recessive manner. The only exceptions are GLUD1, which exhibits autosomal dominant inheritance, ALDH18A1 and CPT2, which can exhibit both autosomal dominant and recessive inheritance, and HCFC1, OTC, and TAZ, which exhibit X-linked inheritance. Pathogenic defects in the genes in this panel include missense, nonsense, splicing site variants, small deletions, small insertions/duplications, small indels, and exon-level large deletions (Human Gene Mutation Database).

The genes included in this test are associated with disorders that can be broadly classified into several categories based on the pathways within the cell that are disrupted:

Disorders of Ammonia Detoxification: ARG1, ASL, ASS1, CA5A, CPS1, NAGS, OTC, SLC25A13, SLC25A15

Disorders of Amino Acid Metabolism and/or Transport: ALDH18A1, BCKDHA, BCKDHB, DBT, DLD, GLUD1, GLUL, HMGCL, IVD, MCCC1, MCCC2, MLYCD, MMUT, OAT, PCCA, PCCB, SLC7A7 

Disorders of Carnitine Metabolism: CPT1A, CPT2, SLC22A5, SLC25A20

Disorders of Cobalamin Metabolism: ABCD4, HCFC1, LMBRD1, MMAA, MMAB, MMACHC, MMADHC, MTR, MTRR

Disorders of Fatty Acid Oxidation and Transport, and Ketone Metabolism: ACADM, ACADS, ACADVL, ACAT1, HADH, HADHA, HADHB, HMGCS2, TANGO2

Disorders of Biotin, Pantothenate, or Riboflavin Metabolism: BTD, ETFA, ETFB, ETFDH, HLCS, SLC25A42

Mitochondrial Related DisordersFBXL4, MRPS22, SERAC1, TAZ, TMEM70, UQCRC2

Miscellaneous DisordersCAD (pyrimidine metabolism), NBAS (associated with infantile liver failure syndrome 2), PC 

Of the genes included in this test, no large copy number variants (gross deletions or duplications/insertions) have been observed in the ABCD4, ACADS, ACADVL, CAD, CPT2, DLD, ETFB, GLUD1, GLUL, HCFC1, MCCC2,  MMAB, MMADHC, MRPS22, MTR, MTRR, NAGS, PC, SLC25A42,  or UQCRC2 genes. Large copy number variants have been reported as a relatively common cause of disease in the BCKDHA, BCKDHB, CA5A, DBT, LMBRD1, OTC, PCCA, SLC22A5, SLC25A13, SLC7A7, TANGO2, and TAZ genes. Copy number variants have been reported as a more rare cause of disease in the remaining genes on this panel. 

It should also be noted that, to our knowledge, de novo variants are not commonly reported for the majority of genes in this panel, although they have been reported in ALDH18A1, GLUD1, HCFC1, OTC and TAZ.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity of this specific grouping of genes is difficult to estimate as we are unaware of any reports in the literature in which these genes have been sequenced together in a patient cohort with hyperammonemia as the primary indication for testing. The clinical sensitivity of sequencing the individual genes is high in patient groups with biochemical and/or enzymatic diagnoses of the relevant disorders; details are available on the individual gene test description pages. Analytical sensitivity is expected to be high as the majority of variants reported in these genes are detectable via direct sequencing.

Of note, Martín-Hernández et al. (2014. PubMed ID: 25433810) reported an observational study of 104 patients diagnosed with urea cycle disorders. Among their patient cohort, 67 were diagnosed with OTC deficiency, 22 with ASS1 deficiency, 10 with ASL deficiency, 2 with ARG1 deficiency, 2 with CPS1 deficiency, and 1 with NAGS deficiency. 

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.5% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with hyperammonemia are good candidates for this test, especially if other external causes of hyperammonemia (such as infection or hepatic failure) have been ruled out. Adults presenting with encephalopathy are also good candidates for this test.

Diseases

Name Inheritance OMIM ID
3 Methylcrotonyl-CoA Carboxylase 1 Deficiency AR 210200
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency AR 246450
3-Methylcrotonyl CoA Carboxylase 2 Deficiency AR 210210
3-Methylglutaconic Aciduria Type 2 XL 302060
3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-like Syndrome AR 614739
Alpha-Methylacetoacetic Aciduria AR 203750
Arginase Deficiency AR 207800
Argininosuccinate Lyase Deficiency AR 207900
Autosomal Recessive Cutis Laxa Type 3A AR 219150
Carnitine Palmitoyltransferase I Deficiency AR 255120
Carnitine Palmitoyltransferase II Deficiency, Infantile AR 600649
Carnitine Palmitoyltransferase II Deficiency, Late-Onset AD,AR 255110
Carnitine Palmitoyltransferase II Deficiency, Lethal Neonatal AR 608836
Carnitine-Acylcarnitine Translocase Deficiency AR 212138
Citrin Deficiency AR 605814
Citrullinemia Type I AR 215700
Citrullinemia Type II AR 603471
Combined Oxidative Phosphorylation Deficiency 5 AR 611719
Congenital Hyperammonemia, Type I AR 237300
Cutis Laxa, Autosomal Dominant 3 AD 616603
Deficiency Of 3-Hydroxyacyl-CoA Dehydrogenase AR 231530
Deficiency Of Butyryl-CoA Dehydrogenase AR 201470
Dihydrolipoamide dehydrogenase deficiency AR 246900
Epileptic Encephalopathy, Early Infantile, 50 AR 616457
Glutamine Deficiency, Congenital AR 610015
Glutaric Aciduria, Type 2 AR 231680
Gyrate Atrophy of Choroid and Retina with or without Ornithinemia AR 258870
Homocystinuria-Megaloblastic Anemia Due To Defect In Cobalamin Metabolism, cblE Complementation Type AR 236270
Homocystinuria-Megaloblastic Anemia Due To Defect In Cobalamin Metabolism, cblG Complementation Type AR 250940
Hyperammonemia due to carbonic anhydrase VA deficiency AR 615751
Hyperammonemia, Type III AR 237310
Hyperinsulinemic Hypoglycemia, Familial 6 AD 606762
Hyperinsulinemic Hypoglycemia, Familial, 4 AR 609975
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome AR 238970
Infantile Liver Failure Syndrome 2 AR 616483
Isovaleryl-CoA Dehydrogenase Deficiency AR 243500
Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency AR 609016
Lysinuric Protein Intolerance AR 222700
Malonyl-CoA Decarboxylase Deficiency AR 248360
Maple Syrup Urine Disease AR 248600
Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency AR 201450
Mental Retardation, X-Linked 3 (Methylmalonic Acidemia and Homocysteinemia, cblX Type) XL 309541
Metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression AR 618416
Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration AR 616878
Methylmalonic Aciduria and Homocystinuria, cblC Type AR 277400
Methylmalonic Aciduria and Homocystinuria, cblD Type AR 277410
Methylmalonic Aciduria and Homocystinuria, cblF Type AR 277380
Methylmalonic Aciduria and Homocystinuria, cblJ Type AR 614857
Methylmalonic Aciduria Cbla Type AR 251100
Methylmalonic Aciduria Cblb Type AR 251110
Methylmalonic Aciduria Due To Methylmalonyl-CoA Mutase Deficiency AR 251000
Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency AR 605911
Mitochondrial Complex III Deficiency, Nuclear Type 5 AR 615160
Mitochondrial Complex V (ATP Synthase) Deficiency, Nuclear Type 2 AR 614052
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type) AR 615471
Multiple Carboxylase Deficiency, Juvenile Onset AR 253260
Multiple Carboxylase Defiency, Early Onset AR 253270
Ornithine Carbamoyltransferase Deficiency XL 311250
Propionic Acidemia AR 606054
Pyruvate Carboxylase Deficiency AR 266150
Short stature, Optic nerve atrophy, and Pelger-Huet anomaly AR 614800
Spastic Paraplegia 9A AD 601162
Spastic Paraplegia 9B AR 616586
Systemic Carnitine Deficiency AR 212140
Trifunctional Protein Deficiency AR 609015
Very Long Chain Acyl-CoA Dehydrogenase Deficiency AR 201475

Related Test

Name
PGxome®

Citations

  • Ali et al. 2020. PubMed ID: 32491436
  • Ferreira et al. 2020. PubMed ID: 25299040
  • Häberle. 2013. PubMed ID: 23628343
  • Human Gene Mutation Database (Bio-base).
  • LaBuzetta et al. 2010. PubMed ID: 20920686
  • Lachmann and Murphy. 2016. Emergencies. In: Hollak and Lachmann, editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 541-551.
  • Lichter-Konecki et al. 2016. PubMed ID: 24006547
  • Martín-Hernández et al. 2014. PubMed ID: 25433810
  • Monch. 2015. Deficiencies of the Urea Cycle - Clinical Significance and Therapy. Bremen: UNI-MED. 91 p.
  • Nyhan et al. 2017. Work-Up of the Patient with Hyperammonemia. In: Hoffmann G.F., Nyhan W.L. and Zschocke J., editors. Inherited Metabolic Diseases: A Clinical Approach. Berlin: Springer, p 113-117.
  • Rabier. 2016. Hyperammonemia. In: Hollak C.E.M. and Lachmann R.H., editors. Inherited Metabolic Disease in Adults: A Clinical Guide. New York: Oxford University Press, p 541-551.
  • Sabbah. 2020. PubMed ID: 33001359
  • Sloan et al. 2018. PubMed ID: 20301503

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

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