Citrullinemia, Type I via ASS1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesPrice Test CPT CodeGene CPT Codes Copy CPT Codes STAT Prenatal
9535 ASS1$890 8140681406,81479 Add to Order

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

A 25% additional charge will be applied to STAT orders. View STAT turnaround times here.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Targeted Testing

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

Turnaround Time

18 days on average


Genetic Counselors


Clinical Features and Genetics

Clinical Features

Urea cycle defects are characterized by hyperammonemia, encephalopathy and respiratory alkalosis (Brusilow and Horwich 2014). Eight clinical disorders have been described involving defective urea cycle enzymes or transporter proteins: N-acetylglutamate synthase deficiency, carbamoyl phosphate synthetase I deficiency, ornithine transcarbamolase deficiency, argininosuccinate synthetase deficiency (also known as citrullinemia type I), argininosuccinate lyase deficiency, arginase deficiency, citrin deficiency (also known as citrullinemia type II) and hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome (Ah Mew et al. 2015).

Type I citrullinemia presents in the neonate following protein intake with massively elevated serum citrulline levels resulting in hyperammonemia. Patients exhibit lethargy, refusal to feed, vomiting, and tachypnea or stroke (Häberle et al. 2003; Ah Mew et al. 2015; Quinonez and Thoene 2016). Untreated, argininosuccinate synthetase deficiency can lead to increased intracranial pressure, increased neuromuscular tone, seizures, loss of consciousness, and death (Quinonez and Thoene 2016). A milder adult-onset form of the disease has also been described (Häberle et al. 2003; Martín-Hernández et al. 2014). Clinical signs of the milder form include recurrent lethargy, somnolence, mental retardation, and chronic or recurrent hyperammonemia. Treatment includes a protein restricted diet and sodium benzoate to scavenge ammonia (Quinonez and Thoene 2016).


Type I or classic citrullinemia is an autosomal recessive disorder. Pathogenic variants in the ASS1 gene cause both the severe neonatal and milder adult onset forms of citrullinemia type I (Häberle et al. 2003; Martín-Hernández et al. 2014). The ASS1 gene encodes argininosuccinate synthetase, a urea cycle enzyme that converts citrulline and aspartate to argininosuccinate. Missense variants are the predominant type of disease-causing variants in ASS1, though nonsense, splicing, small deletions and insertions and gross deletions have been reported as well (Gao et al. 2003; Martín-Hernández et al. 2014; Human Gene Mutation Database). Pathogenic variants are spread throughout the gene and most reported variants appear to be private. However, a few variants have been more commonly reported, such as c.421-2A>G (common in Japanese and Korean patients), c.535T>C (p.Trp179Arg), c.910C>T (p.Arg304Trp), c.970G>A (p.Gly324Ser) and c.1168G>A (p.Gly390Arg) (Engel et al. 2009; Woo et al. 2014).

Type II Citrullinemia, a multisystem disorder, is caused by pathogenic variants in the SLC25A13 gene and has clinically and biochemically distinct features (Kobayashi et al. 2014). Testing for both types of citrullinemia is available individually as well as via our Urea Cycle Disorders NextGen Sequencing (NGS) panel.

Testing Strategy

This test provides full coverage of all coding exons of the ASS1 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.

This test also includes coverage for the intronic variant designated as c.174-1119G>A.

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

Clinical Sensitivity - Sequencing with CNV

Test sensitivity should be very high in the newborn with clinical symptoms of ammonium intoxication and a plasma amino acid profile suggestive of argininosuccinate synthetase deficiency. Gao et al. (2003) reported 2 alleles in 100% of the 38 patients studied, and Häberle et al. (2003) reported 2 alleles in 100% of the 21 patients (from 17 families) they studied. Quinonez and Thoene (2016) report a clinical sensitivity of ~96%.

Although the clinical sensitivity of deletion/duplication testing is expected to be relatively low, at least four gross deletions have been reported in the ASS1 gene (Human Gene Mutation Database).

Indications for Test

A plasma ammonia concentration of 150 μmol/L or higher, associated with a normal anion gap and a normal serum glucose concentration is a strong indication for the presence of a urea cycle defect (Ah Mew et al. 2015). Plasma citrulline levels can differentiated 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). Elevated plasma citrulline and absent argininosuccinate is indicative of absent or reduced argininosuccinate synthetase activity. In the mild form, plasma citrulline levels may be near the upper limit of normal. Family members of patients known to have ASS1 variants are also good candidates for this test, and we will sequence the ASS1 gene to determine carrier status.


Official Gene Symbol OMIM ID
ASS1 603470
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Citrullinemia Type I AR 215700

Related Tests

Hyperammonemia Panel
Urea Cycle Disorders Panel


  • Ah Mew N. et al. 2015. Urea Cycle Disorders Overview. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301396
  • Brusilow S.W. and Horwich A.L. 2014. Urea Cycle Enzymes. Online Metabolic & Molecular Bases of Inherited Disease, New York, NY: McGraw-Hill.
  • Engel K. et al. 2009. Human Mutation. 30: 300-7. PubMed ID: 19006241
  • Gao H.Z. et al. 2003. Human Mutation. 22: 24-34. PubMed ID: 12815590
  • Häberle J. et al. 2003. Molecular Genetics and Metabolism. 80: 302-6. PubMed ID: 14680976
  • Human Gene Mutation Database (Bio-base).
  • Kobayashi K. et al. 2014. Citrin Deficiency. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301360
  • Martín-Hernández E. et al. 2014. Orphanet Journal of Rare Diseases. 9: 187. PubMed ID: 25433810
  • Quinonez S.C. et al. 2016. Citrullinemia Type I. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301631
  • Woo H.I. et al. 2014. Clinica Chimica Acta; International Journal of Clinical Chemistry. 431: 1-8. PubMed ID: 24508627


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.

Requisition Form

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

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Specimen Types

Specimen Requirements and Shipping Details

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