Tyrosinemia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
5011 FAH 81406,81479 Order Options and Pricing
GSTZ1 81479,81479
HPD 81479,81479
TAT 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
5011Genes x (4)81479 81406, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

Tyrosinemia is an inborn error in the metabolism of tyrosine, resulting in elevated levels of tyrosine and derivative metabolites. Succinylacetone is elevated in tyrosinemia type I, but not in types II or III. Tyrosinemia is caused by pathogenic variants in the FAH, TAT, or HPD genes (Sniderman King et al. 2017. PubMed ID: 20301688). In addition, hypersuccinylacetonemia is observed in the clinically benign disorder maleylacetoacetate isomerase deficiency, caused by variants in the GSTZ1 gene (Yang et al. 2017. PubMed ID: 27876694).

Type I tyrosinemia is caused by pathogenic variants in the FAH gene. The first clinical signs usually appear in newborns with severe liver pathology. 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; Sniderman King et al. 2017. PubMed ID: 20301688).

Tyrosinemia Type II, also known as Oculocutaneous Tyrosinemia or Richner-Hanhart syndrome, is caused by pathogenic variants in the TAT gene. Affected patients present with eye, skin and neurologic symptoms. Typically, the ocular symptoms are the first to appear and are usually observed during the first year of life. Skin abnormalities, which affect approximately 80% of patients and usually arise after the first year of life, are most commonly painful palmoplantar keratoderma. Lastly, over 60% of affected patients present with intellectual disability, which can range from a mild decrease in intelligence to severe intellectual disability associated with microcephaly and other organ abnormalities (Charfeddine et al. 2006. PubMed ID: 16574453; Mitchell et al. 2014; Sniderman King et al. 2017. PubMed ID: 20301688).

Both tyrosinemia type III and Hawkinsinuria are rare inborn errors of tyrosine metabolism caused by pathogenic variants in the HPD gene (Mitchell et al. 2014). The onset for both disorders is in infancy. Very few patients have been reported with tyrosinemia type III, and thus far a consistent clinical picture has not emerged for this disorder. However, the symptoms most commonly reported in affected patients have been ataxia, developmental delay, intellectual disability and behavior abnormalities (Rüetschi et al. 2000. PubMed ID: 10942115; Tomoeda et al. 2000. PubMed ID: 11073718; Item et al. 2007. PubMed ID: 17560158; Mitchell et al. 2014).

Variants in the GSTZ1 gene have been shown to lead to maleylacetoacetate isomerase deficiency, resulting in hypersuccinylacetonemia (Yang et al. 2017. PubMed ID: 27876694). Elevated succinylacetone has been considered to be pathognomonic for tyrosinemia type I, and thus these individuals were initially flagged for follow up studies and possible initiation of treatment for tyrosinemia type I. As maleylacetoacetate isomerase deficiency is considered a clinically benign disorder, it is useful to be able to distinguish between individuals with hypersuccinylacetonemia as a result of GSTZ1 variants versus those with true tyrosinemia type I.

Genetics

Tyrosinemia types I, II and III are autosomal recessive disorders. Variants in the FAH gene are the genetic cause of type I tyrosinemia, which is the most commonly reported genetic tyrosinemia. Pathogenic variants include missense, nonsense, splicing, small deletions, small indels, and at least one gross deletion (Human Gene Mutation Database). Founder mutations have been identified in Ashkenazi Jews (c.782 C>T, or p.Pro261Leu; Elpeleg et al. 2002. PubMed ID: 11754109) and French Canadians (c.1062+5G>A; Grompe et al. 1994. PubMed ID: 8028615). The overall prevalence of tyrosinemia type I is estimated at ~1:100,000 – 1:120,000. This number is higher in Scandinavian countries (~1:60,000 – 1:74,000) and as high as 1:1,846 births in the Saguenay-Lac Saint-Jean region of Quebec (Sniderman King et al. 2017. PubMed ID: 20301688).

Variants in the TAT gene are the genetic cause of type II tyrosinemia. To date, over 30 causative variants have been reported in the TAT gene. The majority of reported variants are missense, although nonsense, splice site, small deletions and insertions, indels and gross deletions have all been reported (Human Gene Mutation Database).

Both tyrosinemia type III and Hawkinsinuria are caused by defects in the HPD gene. Tyrosinemia type III is an autosomal recessive disorder whereas Hawkinsinuria is an autosomal dominant disorder. To date, fewer than 10 pathogenic variants have been reported in the HPD gene. The majority of the reported variants are missense changes, though a few nonsense and splice variants have also been reported (Human Gene Mutation Database).

Fewer than five variants in GSTZ1 have been reported in association with autosomal recessive hypersuccinylacetonemia. Two of these variants were missense, one was nonsense, and one was an intronic variant predicted to create a novel splice acceptor site (Yang et al. 2017. PubMed ID: 27876694).

The FAH, HPD, TAT, and GSTZ1 genes all encode enzymes in the phenylalanine/tyrosine metabolic pathway. TAT encodes tyrosine aminotransferase, which is responsible for the conversion of tyrosine to 4-hydroxyphenylpyruvic acid. The 4-hydroxyphenylpyruvic acid is subsequently converted to homogentisic acid by the action of the 4-hydroxyphenylpyruvic acid dioxygenase enzyme, which is encoded by the HPD gene. Further in the pathway, the enzyme maleylacetoacetate isomerase (encoded by the GSTZ1 gene) converts maleylacetoacetic acid to fumarylacetoacetic acid, which is then converted to fumaric acid and acetoacetic acid by the fumarylacetoacetic acid hydrolase enzyme (encoded by FAH) (Sniderman King et al. 2017. PubMed ID: 20301688; Yang et al. 2017. PubMed ID: 27876694).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical Sensitivity - Sequencing with CNV PGxome

Although the overall sensitivity of this test panel is not precisely known, nearly all pathogenic variants reported for the genes in this panel are of the type which can be detected by sequencing with CNV analysis.

The most commonly affected gene in tyrosinemia patients is FAH. Over 95% of causative FAH variants have been reportedly detected by gene sequencing (Dursun et al. 2011. PubMed ID: 23430822; Imtiaz et al. 2011. PubMed ID: 21764616; Sniderman King et al. 2017. PubMed ID: 20301688). At least one pathogenic gross deletion encompassing multiple FAH exons has been reported (Park et al. 2009. PubMed ID: 19569981).

For the HPD and TAT genes, clinical sensitivity is difficult to estimate because only a small number of patients have been reported. Analytical sensitivity should be high because the great majority of variants reported are expected to be detectable via this test methodology.

As only a few patients have been reported to date, it is uncertain what proportion of individuals identified based on hypersuccinylacetonemia on newborn screening tests would be expected to harbor causative variants in GSTZ1.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

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

Indications for Test

Individuals with biochemical or enzyme assay test results consistent with tyrosinemia are good candidates for this test, as are those with clinical features consistent with tyrosinemia.

Genes

Official Gene Symbol OMIM ID
FAH 613871
GSTZ1 603758
HPD 609695
TAT 613018
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
PGxome®
Tyrosinemia Type III and Hawkinsinuria via the HPD Gene
Tyrosinemia, Type I via the FAH Gene
Tyrosinemia, Type II via the TAT Gene

Citations

  • Charfeddine et al. 2006. PubMed ID: 16574453
  • Dursun et al. 2011. PubMed ID: 23430822
  • Elpeleg et al. 2002. PubMed ID: 11754109
  • Grompe et al. 1994. PubMed ID: 8028615
  • Human Gene Mutation Database (Biobase).
  • Imtiaz et al. 2011. PubMed ID: 21764616
  • Item et al. 2007. PubMed ID: 17560158
  • Mitchell et al. 1990. PubMed ID: 2153931
  • Mitchell et al. 2014. Hypertyrosinemia. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID).
  • Park et al. 2009. PubMed ID: 19569981
  • Rüetschi et al. 2000. PubMed ID: 10942115
  • Sniderman King et al. 2017. PubMed ID: 20301688
  • Tomoeda et al. 2000. PubMed ID: 11073718
  • Yang et al. 2017. PubMed ID: 27876694

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.

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

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ORDER OPTIONS

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2) Select Additional Test Options

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

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