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Citrullinemia, Type I via ASS1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9535 ASS1 81406 81406,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9535ASS181406 81406(x1), 81479(x1) $890 Order Options and Pricing

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.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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

  • McKenna Kyriss, PhD

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).

Genetics

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.

Clinical Sensitivity - Sequencing with CNV PGxome

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).

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

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).

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.

Gene

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

Disease

Name Inheritance OMIM ID
Citrullinemia Type I AR 215700

Related Test

Name
Urea Cycle Disorders Panel

Citations

  • 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/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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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