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Elevated Tyrosine and Succinylacetone/Tyrosinemia Type I via the FAH 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
FAH 81406 81406,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9591FAH81406 81406,81479 $990 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 platform).

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

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

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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

Newborn screening (NBS) tests are performed soon after birth with the goal of identifying individuals that may be affected by certain disorders before disease-related disability or death occurs. Appropriate medical management beginning early in life can prevent all or many symptoms in the affected individuals (Watson et al. 2006. PubMed ID: 16783161; https://www.cdc.gov/newbornscreening/). While NBS is required within all states and territories in the United States, individual state or territory public health departments determine which conditions are included on the NBS panel (https://www.babysfirsttest.org/newborn-screening/states). NBS protocols outside of the United States vary from country to country. At a minimum, all core conditions on the Recommended Uniform Screening Panel (RUSP) should be included on NBS panels within the United States. In addition, NBS testing may also include secondary conditions, which are disorders that can be detected as part of the differential diagnosis of a core condition (https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp). Following an abnormal NBS result, follow up diagnostic testing is indicated. Such testing may include biochemical methodologies (for example, urine organic acid analysis or plasma acylcarnitine analysis), enzyme assays, and/or molecular genetic testing.

This test is appropriate for individuals with NBS results showing elevated tyrosine and succinylacetone, which can indicate a deficiency of the fumarylacetoacetate hydrolase (FAH) enzyme. FAH deficiency is a core condition on the RUSP. 

Individuals with FAH deficiency may be unaffected during the newborn period but if untreated, generally develop failure to thrive, liver disease, and renal failure within the first year of life (King et al. 2017. PubMed ID: 20301688; https://www.acmg.net/PDFLibrary/Tyrosine.pdf). Some patients present after the newborn period with rickets and failure to thrive secondary to hepatic and renal dysfunction. A significant number of patients have neurological symptoms including peripheral neuropathy characterized by severe pain with extensor hypertonia, muscle weakness, paralysis requiring ventilation, and self-mutilation (Mitchell et al. 1990. PubMed ID: 2153931). If untreated, death usually occurs before the age of ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma (King et al. 2017. PubMed ID: 20301688). Effective treatment is achieved with nitisinone (NTBC) along with avoidance of dietary phenylalanine and tyrosine. Liver transplantation may be indicated in cases with severe liver damage or hepatocellular carcinoma (Holme. 1998. PubMed ID: 9728331).

The overall prevalence of FAH deficiency is estimated at ~1/100,000-120,000, though it is significantly higher in Scandinavian countries (~1/74,000), Finland (~1/60,000), and Quebec (~1/16,000, and 1/1,846 live births in the Saguenay-Lac Saint-Jean region of Quebec) (King et al. 2017. PubMed ID: 20301688).

Genetics

Fumarylacetoacetate hydrolase (FAH) deficiency, also known as hereditary tyrosinemia type I (HT1), is an autosomal recessive disorder. Over 100 pathogenic variants have been reported in the FAH gene in the Human Gene Mutation Database (HGMD, https://www.hgmd.cf.ac.uk/), with approximately half being missense changes. The remaining reported variants are nonsense, splice site, and small insertion/deletion variants. Copy number variants (CNVs) have only rarely been reported (Park et al. 2009. PubMed ID: 19569981). Several founder variants have been reported in a variety of populations: the Ashkenazi Jewish population (c.782C>T, p.Pro261Leu), the Finnish population (c.786G>A, p.Trp262*), the French Canadian and Northern European populations (c.1062+5G>A), the Pakistani population (c.192G>T, p.Gln64His), the Scandinavian population (c.1009G>A, p.Gly337Ser), the Turkish population (c.698A>T, p.Asp223Val), and the Southern European population (c.554-1G>T) (King et al. 2017. PubMed ID: 20301688). To our knowledge, de novo variants in FAH have not been reported. 

Pathogenic variants in the FAH gene lead to disruption of the fumarylacetoacetate hydrolase enzyme, the enzyme that catalyzes the final step in tyrosine catabolism. The precursor metabolite, fumarylacetoacetate, accumulates in hepatocytes in the absence of FAH activity. This results in cellular damage and diversion to succinylacetone, a reactive metabolite known to interfere with hepatic enzymes (Lindblad et al. 1977. PubMed ID: 270706). FAH deficiency results in elevation of tyrosine and succinylacetone, as well as possible elevation of methionine and phenylalanine and 5-aminolevulinic acid (King et al. 2017. PubMed ID: 20301688; http://www.iembase.com/disorder/19).

Clinical Sensitivity - Sequencing with CNV PGxome

Based on studies of individuals with a diagnosis of hereditary tyrosinemia type I, approximately 90-100% of expected FAH variants are identified by molecular testing (Bergman et al. 1998. PubMed ID: 9633815; Arranz et al. 2002. PubMed ID: 12203990; Baydakova et al. 2018. PubMed ID: 30414057; Ibarra-González et al. 2019. PubMed ID: 31568711).

Testing Strategy

This test provides full coverage of all coding exons of the FAH 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).

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

Patients with elevated tyrosine and succinylacetone on NBS are good candidates for this test. Patients with reduced fumarylacetoacetate hydrolase enzyme activity are candidates for this test, as are those with clinical features of hereditary tyrosinemia type I. We will also sequence the FAH gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
FAH 613871
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Tyrosinemia Type I AR 276700

Related Tests

Name
PGmaxTM - Comprehensive Inherited Metabolic Disorders and Mitochondrial Disorders (Nuclear Genes only) Panel
Tyrosinemia Panel

Citations

  • Arranz et al. 2002. PubMed ID: 12203990
  • Baydakova et al. 2018. PubMed ID: 30414057
  • Bergman et al. 1998. PubMed ID: 9633815
  • Holme. 1998. PubMed ID: 9728331
  • http://www.iembase.com/disorder/19
  • https://www.acmg.net/PDFLibrary/Tyrosine.pdf
  • https://www.babysfirsttest.org/newborn-screening/states
  • https://www.cdc.gov/newbornscreening/
  • https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp)
  • Human Gene Mutation Database (Biobase).
  • Ibarra-Gonz├ílez et al. 2019. PubMed ID: 31568711
  • King et al. 2017. PubMed ID: 20301688
  • Lindblad et al. 1977. PubMed ID: 270706
  • Mitchell et al. 1990. PubMed ID: 2153931
  • Park et al. 2009. PubMed ID: 19569981
  • Watson et al. 2006. PubMed ID: 16783161

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

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