• Test code: 06149
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Tyrosinemia Panel

Test description

The Invitae Tyrosinemia Panel analyzes the FAH, TAT, and HPD genes, which encode enzymes responsible for tyrosine metabolism. This test is useful for the diagnosis of patients whose clinical symptoms, abnormal newborn screening results, or biochemical findings indicate tyrosinemia. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Additionally, identification of disease-causing variants provides accurate genetic counseling and reproductive risks, risk assessment and carrier status of at-risk relatives.

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Primary panel (3 genes)
  • tyrosinemia
    • tyrosinemia type I (FAH deficiency)
    • tyrosinemia type II (TAT deficiency)
    • tyrosinemia type III (HPD deficiency)
    • Hawkinsinuria

There are three types of tyrosinemia, each is caused by the deficiency of a different enzyme involved in tyrosine metabolism and each manifests distinctive symptoms. Tyrosinemia type I is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase encoded by the FAH gene. Clinical presentation of type I is highly variable and symptoms can manifest at any time from one month of age to adulthood. The primary symptoms are progressive liver and kidney dysfunction. Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The urine has an odor of cabbage or rancid butter. In addition, there is an increased risk of hepatocellular carcinoma. Tyrosinemia type II is caused by a deficiency of the enzyme tyrosine aminotransferase encoded by the TAT gene. Clinical characteristics of type II include ocular lesions, skin lesions, or neurological complications. Symptoms usually present in infancy but can manifest at any age. Tyrosinemia type III is caused by a deficiency of the enzyme 4-Hydroxyphenylpyruvate dioxygenase encoded by the HPD gene. Type III is very rare and the full clinical spectrum of this condition is unknown. Many type III individuals present neurological symptoms and intellectual impairment is a common long-term complication.

Patients with tyrosinemia I are treated with Nitisinone (NTBC). Liver transplantation is the treatment of choice in some children who present with liver failure or fail treatment with NTBC. Dietary restriction of tyrosine is also used to treat tyrosinemia.

Other causes of elevated plasma may include transient tyrosinemia of the newborn or liver disease. Transient tyrosinemia of the newborn is due to late fetal maturation of the enzyme 4-hydroxyphenylpyruvate dioxygenase. It is generally considered clinically benign a condition that usually spontaneously resolves within a few months. It may affect up to 10% of full term newborns and a higher percentage of premature infants and is frequently detected via newborn screening. In addition, non-specific elevation of plasma tyrosine and other amino acids can occur secondary to liver disease. Evaluation of liver function and exclusion of treatable metabolic disorders such as tyrosinemia type 1 may be indicated in these situations.

For patients with a clinical and biochemical diagnosis of tyrosinemia, the detection rate of pathogenic variants in one of these three genes is greater than 90%.

Tyrosinemia is inherited in an autosomal recessive manner. The HPD gene also causes Hawkinsinuria which is inherited in an autosomal dominant manner.

Tyrosinemia has an incidence of 1:100,000 to 1:120,000 worldwide.

  1. Dursun, A, et al. Mutation spectrum of fumarylacetoacetase gene and clinical aspects of tyrosinemia type I disease. JIMD Rep. 2011; 1:17-21. PMID: 23430822
  2. Charfeddine, C, et al. Clinical and mutational investigations of tyrosinemia type II in Northern Tunisia: identification and structural characterization of two novel TAT mutations. Mol. Genet. Metab. 2006; 88(2):184-91. PMID: 16574453
  3. Maydan, G, et al. TAT gene mutation analysis in three Palestinian kindreds with oculocutaneous tyrosinaemia type II; characterization of a silent exonic transversion that causes complete missplicing by exon 11 skipping. J. Inherit. Metab. Dis. 2006; 29(5):620-6. PMID: 16917729
  4. Hühn, R, et al. Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II. Hum. Genet. 1998; 102(3):305-13. PMID: 9544843
  5. Rüetschi, U, et al. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III. Hum. Genet. 2000; 106(6):654-62. PMID: 10942115
  6. Item, CB, et al. Manifestation of hawkinsinuria in a patient compound heterozygous for hawkinsinuria and tyrosinemia III. Mol. Genet. Metab. 2007; 91(4):379-83. PMID: 17560158
  7. Ota, VK, et al. PRODH polymorphisms, cortical volumes and thickness in schizophrenia. PLoS ONE. 2014; 9(2):e87686. PMID: 24498354
  8. McKiernan, PJ, et al. Outcome of children with hereditary tyrosinaemia following newborn screening. Arch. Dis. Child. 2015; 100(8):738-41. PMID: 25564536
  9. Sniderman, King, L, et al. Tyrosinemia Type I. 2006 Jul 24. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301688
  10. Chakrapani A, Gissen P, McKiernan P. Disorders of the Urea Cycle and Related Enzymes. 5th ed. Heidelberg: Springer; 2012. Chapter 18, Disorders of Tyrosine Metabolism; p. 265–276.
  11. American College of Medical Genetics. NBS ACT Sheet. Tyrosinemia. https://www.acmg.net/StaticContent/ACT/Tyrosine.pdf Accessed February 2016.
  12. Tomoeda, K, et al. Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria. Mol. Genet. Metab. 2000; 71(3):506-10. PMID: 11073718
  13. Russo, PA, et al. Tyrosinemia: a review. Pediatr. Dev. Pathol. 2001; 4(3):212-21. PMID: 11370259

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
FAH* NM_000137.2
HPD NM_002150.2
TAT NM_000353.2

FAH: Deletion/duplication analysis is not offered for exon 14.