Ornithine Transcarbamylase Deficiency via the OTC Gene

Urea cycle defects are characterized by hyperammonemia, encephalopathy, and 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 variants have been reported (Yamaguchi et al. Hum Mut 27:626-632, 2006). The majority are missense; however, many nonsense and splice site variants are known as well. Tuchman (Hum Mut 2:174-178, 1993) reported that approximately 10 to 15% of all variants 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.

Yamaguchi et al. (Hum Mut 27:626-632, 2006) reported that variants could be found in approximately 80% of patients. In a study of 341 OTC variants, 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.

This test provides full coverage of all coding exons of the OTC gene 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 full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

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.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).