Ornithine Transcarbamylase Deficiency: OTC Gene Sequencing

Condition Description

Ornithine Transcarbamylase (OTC) deficiency is the most common inherited urea cycle disorder, and is transmitted in an X-linked pattern [1]. The clinical phenotype in affected males as well as heterozygous females shows a spectrum of severity ranging from neonatal hyperammonemic coma to asymptomatic adults. Clinical presentation is complex because male hemizygotes usually present in infancy, while female heterozygotes may be asymptomatic or develop usually milder disease due to skewed X-inactivation[2].

OTC deficiency results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Because no effective secondary clearance system for ammonia exists, disruption of the urea cycle results in a rapid development of catabolism which may cause cerebral edema, lethargy, anorexia, hyper-/hypoventilation, hypothermia, seizures, neurologic posturing, coma and death, if untreated. Pharmacologic management with sodium benzoate/phenylacetate (Buphenyl) and protein restriction in diet may prevent or alleviate primary complications [3].

OTC deficiency involves an impairment of the reaction that leads to condensation of carbamyl phosphate and ornithine to form citrulline [1]. This impairment leads to reduced ammonia incorporation, which causes symptomatic hyperammonemia and increased urinary excretion of orotic acid. The OTC enzyme is encoded by the OTC gene (Xp21) which is normally expressed in the liver. Heterogeneous mutations have been reported in the OTC gene in individuals with OTC deficiency [4-5]. There is also some evidence for genotype-phenotype correlation [6]. Gene sequence analysis is available to test for mutations in the OTC gene (HU). For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array (ET).

1. Brusilow and Horwich. Urea Cycle Enzymes, in: C.R. Scriver, A.L. Beaudet, W. Sly, D. Valle (Eds.), The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill, New York, 2001, pp. 1916-1925.
2. Smith W. et al. Urea Cycle Disorders: Clinical Presentation Outside the Newborn Period Crit Care Clin 2005, 21:S9-S17.
3. Singh R.H. et al. Nutritional Management of Urea Cycle Disorders. Crit Care Clin 2005, 21:S27-S35.
4. Yamaguchi et al. Mutations and Polymorphisms in the Human Ornithine Transcarbamylase (OTC) Gene. Hum Mutat 2006, 27(7),626-632.
5. Arranz et al. Estimation of the total number of disease-causing mutations in ornithine transcarbamylase (OTC) deficiency. Value of the OTC structure in predicting a mutation pathogenic potential. J Inherit Metab Dis 2007, 30:217-226.
6. McCullough et al. Genotype spectrum of ornithine transcarbamylase deficiency: correlation with the clinical and biochemical phenotype. Am J Med Genet 2000, 93: 313-319.
7. Brusilow and Maestri. Urea cycle disorders: diagnosis, pathophysiology and therapy. Adv Pediatr 1996, 43:127-170.

Genes (1)


This test is indicated for:
  • Confirmation of a clinical/biochemical diagnosis of OTC deficiency
  • Carrier testing in adults with a family history of OTC deficiency


PCR amplification of 10 exons contained in the OTC gene is performed on patient genomic DNA. Direct sequencing of amplification products is performed in both the forward and reverse directions using automated fluorescence dideoxy sequencing methods. Patient gene sequences are compared to a normal reference sequence. Sequence variations are then classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements. Large deletions are not detected by this analysis.


The majority of patients with clinical and biochemical diagnosis of OTC deficiency will have an abnormal DNA test.
Clinical Sensitivity: 26/26 mutations identified in 26 patients [4]; 23/23 mutations identified in 23 patients [5].

Analytical Sensitivity: ~99%

Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with client services (NTD_ATL_CS@eurofins-ntdgenetics.com).
Submit only 1 of the following specimen types

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample. Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.
  • Plasma Amino Acid (AA) Analysis, Urine Organic Acids (OA) including urine orotic acid (OT), and plasma ammonia levels are used in the diagnosis of a patient with OTC deficiency
  • Custom Diagnostic Mutation Analysis (KM) is available to family members if mutations are identified by sequencing.
  • Deletion/Duplication Assay is available separately for individuals where mutations are not identified by sequence analysis. Refer to the test requisition or contact the laboratory for more information.
  • Prenatal testing is available for known familial mutations only. Please call the Laboratory Genetic Counselor before collecting a fetal sample.

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