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  • Test code: 06126
  • 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
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  1. Metabolic Disorders and Newborn Screening
  2. Invitae Elevated Tyrosine Panel

Invitae Elevated Tyrosine Panel

Test description

The Invitae Elevated Tyrosine Panel analyzes FAH, TAT, and HPD, three genes that are associated with elevations of tyrosine levels on newborn screening (NBS), or plasma amino acid analysis. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Age of diagnosis and subsequent metabolic management are some of the most important determinants of long-term outcome. Identification of disease-causing variants provide accurate risk assessment and carrier status for at-risk relatives.

Genes tested

FAH HPD TAT

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Primary panel (3 genes)

FAH HPD TAT

Panel details and technical assay limitations

Clinical information

  • Tyrosinemia
    • Tyrosinemia type I
    • Tyrosinemia type II
    • Tyrosinemia type III
    • Hawkinsinuria

Elevated tyrosine may be detected during newborn screening (NBS) or plasma amino acid analysis due to Tyrosinemia type I, type II, or type III caused by pathogenic variants in enzymes encoded by the FAH, TAT, and HPD genes, respectively. Deficiencies of these enzymes cause elevated levels of tyrosine in the body. 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 the neonatal period to adulthood in an affected individual. The primary effects 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.

Late fetal maturation of 4-hydroxyphenylpyruvate dioxygenase causes transient tyrosinemia, a condition that may affect 10% of full term newborns and a higher percentage of premature infants is generally considered clinically benign. 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.

For considerations for testing please refer to:

  1. 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
  2. Russo, PA, et al. Tyrosinemia: a review. Pediatr. Dev. Pathol. 2001; 4(3):212-21. PMID: 11370259
  3. 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
  4. 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
  5. 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
  6. Hühn, R, et al. Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II. Hum. Genet. 1998; 102(3):305-13. PMID: 9544843
  7. Natt, E, et al. Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Proc. Natl. Acad. Sci. U.S.A. 1992; 89(19):9297-301. PMID: 1357662
  8. 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
  9. 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
  10. American College of Medical Genetics. NBS ACT Sheet. Tyrosinemia. https://www.acmg.net/StaticContent/ACT/Tyrosine.pdf Accessed February 2016.
  11. 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.
  12. Ota, VK, et al. PRODH polymorphisms, cortical volumes and thickness in schizophrenia. PLoS ONE. 2014; 9(2):e87686. PMID: 24498354

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.

Clinical resources
Invitae brochure Metabolic disorders and newborn screening analytes table Metabolic disorders and newborn screening requisition form and gene list
Patient resources
Patient guide: Genetic testing simplified
Test information
Forms page Specimen requirements page

References

  1. American College of Medical Genetics. NBS ACT Sheet. Tyrosinemia. https://www.acmg.net/StaticContent/ACT/Tyrosine.pdf Accessed February 2016.
  2. 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.
  3. 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
  4. 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
  5. Hühn, R, et al. Novel and recurrent tyrosine aminotransferase gene mutations in tyrosinemia type II. Hum. Genet. 1998; 102(3):305-13. PMID: 9544843
  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. 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
  8. Natt, E, et al. Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Proc. Natl. Acad. Sci. U.S.A. 1992; 89(19):9297-301. PMID: 1357662
  9. Ota, VK, et al. PRODH polymorphisms, cortical volumes and thickness in schizophrenia. PLoS ONE. 2014; 9(2):e87686. PMID: 24498354
  10. Russo, PA, et al. Tyrosinemia: a review. Pediatr. Dev. Pathol. 2001; 4(3):212-21. PMID: 11370259
  11. 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
  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

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