Hyperammonemia via the OTC Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
551 OTC$840.00 81405 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity
Yamaguchi et al. (Hum Mut 27:626-632, 2006) reported that mutations could be found in approximately 80% of patients.  In a study of 341 OTC mutations, the same authors found that 43% were associated with neonatal onset, 20% with later onset in males and 35% with manifesting females.  Array CGH should be considered in all patients with normal sequencing results to rule out a deletion.

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 OTC$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Features

Urea cycle defects are characterized by (1) hyperammonemia, (2) encephalopathy, and (3) respiratory alkalosis. Five clinical disorders have been described involving defective urea cycle enzymes: ornithine transcarbamolase deficiency (OMIM 311250), carbamoyl phosphate synthetase I deficiency (OMIM 237300), argininosuccinate synthetase deficiency (OMIM 215700), argininosuccinate lyase deficiency (OMIM 207900), and arginase deficiency (OMIM 207800). Ornithine transcarbamylase (OTC) functions in the liver to generate citrulline from ornithine and carbamoyl phosphate, thus recycling free ammonia. Deficiency of this enzyme leads to elevated ammonia and subsequent ammonia intoxication. Clinical symptoms of hyperammonemia due to OTC deficiency (OMIM 311250) can appear in the neonatal period in patients with significant enzyme deficiency, or as late as adulthood in individuals with partial enzyme deficiency (Finkelstein et al. J Pediat 117:897-902, 1990; Drogari et al. Arch Dis Child 63:1363-1367, 1988). Untreated infants develop cerebral edema leading to lethargy, diminished appetite, seizures, and coma. Patients presenting after the neonatal period may demonstrate irritability, vomiting, lethargy, and coma especially after a high protein meal, or while fasting or during an infection (Oizumi et al. Clin Genet 25:538-542, 1984).


Hyperammonemia due to ornithine transcarbamylase (OTC) deficiency is an X linked recessive disorder. Although most patients are males, carrier females can experience serious symptoms early in life (Rowe at al. New Eng J Med 314:541-547, 1986) or in adulthood (Gilchrist and Coleman Ann Intern Med. 106:556-558, 1987). Approximately 15% of carrier females develop hyperammonemia (Brusilow Prog Liver Dis 13:293-309, 1995). Over 300 OTC mutations have been reported (Yamaguchi et al. Hum Mut 27:626-632, 2006). The majority are missense, however many nonsense and splice site mutations are known as well. Tuchman (Hum Mut 2:174-178, 1993) reported that approximately 10 to 15% of all mutations associated with OTC deficiency were large deletions involving all or part of the OTC gene. By array CGH, Shchelochkov et al. (Mol Genet and Metab 96:97-105, 2009) found deletions in half of their patients with normal OTC gene sequencing results.

Testing Strategy

Ornithine transcarbamylase is coded by exons 1-10 of the OTC gene on chromosome Xp11. Testing is accomplished by amplifying each coding exon and ~10 bp of adjacent noncoding sequence, then determining the nucleotide sequence using standard dideoxy sequencing methods and a capillary electrophoresis instrument. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

This testing also includes coverage for the following intronic or other non-coding OTC variants, as well as ~10 bp of adjacent sequence: c.-366A>G, c.540+265G>A, c.867+1126A>G and c.1005+1091C>G.

Indications for Test

A plasma ammonia concentration of ≥ 150 μmol/L, associated with a normal anion gap and a normal serum glucose concentration is a strong indication for the presence of a urea cycle defect (Summar, GeneReviews, 2005). Plasma citrulline levels can differentiate between defects in proximal urea cycle enzymes (low citrulline; OTC and carbamoyl phosphate synthetase) from distal enzymes (high citrulline; argininosuccinate synthetase, argininosuccinate lyase, and arginase).


Official Gene Symbol OMIM ID
OTC 300461
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Ornithine Carbamoyltransferase Deficiency 311250

Related Tests

Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Hyperammonemia Sequencing Panel
Urea Cycle Disorders Sequencing Panel
X-Linked Intellectual Disability Sequencing Panel with CNV Detection


Genetic Counselors
  • Brusilow, S. W. (1995). "Urea cycle disorders: clinical paradigm of hyperammonemic encephalopathy." Prog Liver Dis 13: 293-309. PubMed ID: 9224507
  • Drogari, E., Leonard, J. V. (1988). "Late onset ornithine carbamoyl transferase deficiency in males." Arch Dis Child 63(11): 1363-7. PubMed ID: 3202644
  • Finkelstein, J. E., (1990). "Late-onset ornithine transcarbamylase deficiency in male patients." J Pediatr 117(6): 897-902. PubMed ID: 2246687
  • Gilchrist, J. M., Coleman, R. A. (1987). "Ornithine transcarbamylase deficiency: adult onset of severe symptoms." Ann Intern Med 106(4): 556-8. PubMed ID: 3826955
  • Marshall L Summar (2011). "Urea Cycle Disorders Overview." PubMed ID: 20301396
  • Oizumi, J., (1984). "Partial ornithine transcarbamylase deficiency associated with recurrent hyperammonemia, lethargy and depressed sensorium." Clin Genet 25(6): 538-42. PubMed ID: 6733950
  • Rowe, P. C., (1986). "Natural history of symptomatic partial ornithine transcarbamylase deficiency." N Engl J Med 314(9): 541-7. PubMed ID: 3945292
  • Shchelochkov, O. A., (2009). "High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH." Mol Genet Metab 96(3): 97-105. PubMed ID: 19138872
  • Tuchman, M. (1993). "Mutations and polymorphisms in the human ornithine transcarbamylase gene." Hum Mutat 2(3): 174-8. PubMed ID: 8364586
  • Yamaguchi, S., (2006). "Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene." Hum Mutat 27(7): 626-32. PubMed ID: 16786505
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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