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Test Code UGT2 UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia

Performing Laboratory

Mayo Medical Laboratories in Rochester

Reporting Name

UGT1A1 Sequence, Hyperbilirubinemia

Specimen Type

Whole Blood EDTA


Specimen Required


Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

 

Container/Tube:

Adults: Lavender top (EDTA)

Pediatrics: Purple microtube

Specimen Volume:

Adults: 3 mL

Pediatrics: 1 mL

Collection Instructions:

1. Send specimen in original tube.

2. If submitting microtube, place inside a larger tube or vial for transport.


Reject Due To

Hemolysis

NA

Lipemia

NA

Icterus

NA

Other

NA

Specimen Stability Information

Specimen Type Temperature Time
Whole Blood EDTA Ambient (preferred)
  Refrigerated 

Specimen Minimum Volume

0.3 mL

Day(s) and Time(s) Performed

Tuesday; Varies

Specimen Retention Time

Whole Blood: 2 weeks Extracted DNA: 2 months

Analytic Time

7 days

Reference Values

An interpretive report will be provided.

Useful For

Identifying individuals who are at risk of hyperbilirubinemia

 

Confirmation of a diagnosis of Gilbert or Crigler-Najjar syndromes

 

Verification of carrier status for Gilbert or Crigler-Najjar syndromes

Testing Algorithm

See UGT1A1 Test-Ordering Algorithm in Special Instructions.

Method Name

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

Test Classification

See Individual Test IDs

CPT Code Information

81350-UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide AI) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
UGT2 UGT1A1 Sequence, Hyperbilirubinemia In Process

 

Result ID Test Result Name Result LOINC Value
UGTSQ UGT, Full Gene Sequencing In Process
89611 UGT1A1 Hyperbilirubinemia Result 34509-0
30985 UGT1A1 Hyperbilirubinemia Interp 69047-9
30986 Reviewed by No LOINC Needed

Clinical Information

Excess levels of bilirubin, which is a by-product of heme, have been associated with deleterious health effects. Uridine diphosphate (UDP)-glycuronosyl transferase 1A1 (UGT1A1) is responsible for bilirubin conjugation with glucuronic acid. This renders the bilirubin water soluble and permits excretion of the bilirubin-glucuronide conjugates in urine.(1) Genetic variants in UGT1A1 may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia.

 

Gilbert syndrome, found in 5% to 10% of the population, is the most common hereditary cause of increased bilirubin and is associated with mild hyperbilirubinemia (bilirubin levels are typically around 3 mg/dL).(2) Gilbert syndrome is caused by a 25% to 50% reduced glucuronidation activity of the UGT1A1 enzyme and characterized by episodes of mild intermittent jaundice and the absence of liver disease.

 

Crigler-Najjar (CN) syndrome types I and II are inherited causes of severe unconjugated hyperbilirubinemia. CN type I is associated with the complete absence of UGT1A1 activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) CN type II is a milder form of hyperbilirubinemia, as compared to CN type I, with at least partial UGT1A1 activity. Phenobarbital, a drug that induces synthesis of a number of hepatic enzymes, is effective in decreasing serum bilirubin levels by approximately 25% in patients with CN type II; CN type I does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause kernicterus, which is bilirubin-induced brain damage. In addition to phenobarbital, treatments of CN may include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation.

 

The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. In this assay, the promoter, exons, exon-intron boundaries, and a region in the distal promoter called the "phenobarbital response enhancer module," which is associated with transcriptional activity of the gene, are assessed for variants.(4)

Interpretation

An interpretive report is provided.

 

UGT1A1 is a pharmacogene and patients with reduced UGT1A1 enzyme activity are at risk for adverse outcomes with certain drugs. The FDA drug labels for nilotinib, pazopanib, and belinostat all contain warnings for an increased risk (incidence) of adverse outcomes in patients who have UGT1A1 alleles associated with reduced activity. The Clinical Pharmacogenetics Implementation Consortium (CPIC) released guidelines for atazanavir treatment, indicating that patients with homozygous UGT1A1 alleles associated with reduced activity or decreased expression should consider an alternate medication due to a significant risk for developing hyperbilirubinemia (jaundice).

Cautions

Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient’s genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing. 

 

UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient's UGT1A1 status.

 

An alternative splice site for exon 5 (referred to as exon 5b) has been discovered and described in the literature. This new exon is described to have a decrease in enzymatic activity (compared with exon 5a: previously known as exon 5), but little is known about the frequency of exon 5b or how it impacts hyperbilirubinemia. Currently, we are not testing or sequencing exon 5b; we continue to monitor the literature for new information on exon 5b.

 

Absence of a detectable gene variant does not rule out the possibility that the patient may have a genetic cause for increased unconjugated bilirubin.

 

Rare variants exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

Clinical Reference

1. Guilemette C: Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Pharmacogenomics J 2003;3:136-158

2. Innocenti F, Grimsley C, Das S, et al: Haplotype structure of the UDP-glucuronosyltransferase 1A1 promoter in different ethnic groups. Pharmacogenetics 2002;12:725-733

3. Costa E, Vieira E, Martins M, et al: Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006;36:91-97

4. Kitagawa C, Ando M, Ando Y, et al: Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 2005;15:35-41

Method Description

Genomic DNA is extracted from whole blood. The UGT1A1 gene is amplified by PCR. The PCR product is then purified and sequenced in both directions using fluorescent dye-terminator chemistry. Sequencing products are separated on an automated sequencer and trace files analyzed for variations in the exons and intron/exon boundaries of the all exons and a region in the distal promoter called the "phenobarbital response enhancer module using mutation detection software and visual inspection (Skierka J, O'Kane D: UDP-glucuronosyltransferase 1A1 and the glucuronidation in oncology applications and hyperbilirubinemia. In Molecular Diagnostics: Techniques and Applications for the Clinical Laboratory. Edited by WW Grody, RM Nakamura, FL Kiechle, CM Strom. Academic Press 2010, pp 409-420)

Profile Information

Test ID Reporting Name Available Separately Always Performed
UGTH UGT1A1 Sequence, Hyperbilirubinemia No Yes
UGTSQ UGT, Full Gene Sequencing No Yes

Genetics Test Information

This test includes gene sequencing of UGT1A1 and is interpreted for the purposes of hyperbilirubinemia syndromes including Gilbert syndrome and Crigler-Najjar syndrome. If UGT1A1 gene sequencing is desired for interpretation related to UGT1A1 drug metabolism (irinotecan and others), order UGTI / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Irinotecan Hypersensitivity.

Forms

1. UGT1A1 Gene Testing for Hyperbilirubinemia Patient Information (T664) is required. See Special Instructions.

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (T576) is available in Special Instructions.