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


Advisory Information


If analysis of only the UGT1A1 promoter TA repeat region (*28, *36, *37 alleles) is desired, see U1A1V / UDP-Glucuronosyl Transferase 1A1 TA Repeat Genotype, UGT1A1.



Shipping Instructions


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



Specimen Required


Multiple whole blood EDTA 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.

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube:

Adults: Lavender top (EDTA)

Pediatrics: Purple microtube

Specimen Volume:

Adults: 3 mL

Pediatrics: 1 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred) 9 days/Refrigerated 30 days

 

Specimen Type: Saliva

Patient Preparation: Patient should not eat, drink, smoke, or chew gum 30 minutes prior to collection.

Supplies: Saliva Swab Collection Kit (T786: fees apply)

Container/Tube: Saliva Swab Collection Kit (T786)

Specimen Volume: One swab

Collection Instructions: Collect and send specimen per kit instructions.

Specimen Stability Information: Ambient 30 days

 

Specimen Type: DNA

Container/Tube: 2 mL screw top tube

Specimen Volume: 100 mcL (microliters)

Collection Instructions:

1. The preferred volume is 100 mcL at a concentration of 50 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated


Forms

1. 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.

2. UGT1A1 Gene Testing Patient Information (T664) is requested. See Special Instructions.

3. If not ordering electronically, complete, print, and send an Oncology Test Request Form (T729) with the specimen. (http://www.mayomedicallaboratories.com/it-mmfiles/oncology-request-form.pdf)

Secondary ID

65428

Useful For

Identifying individuals who are at increased risk of adverse drug reactions with drugs that are metabolized by UGT1A1, including irinotecan, atazanavir, nilotinib, pazopanib, and belinostat

 

Identifying individuals who are at risk of hyperbilirubinemia

 

Follow-up testing for individuals with a suspected UGT1A1 variant, who had negative TA repeat region testing

 

Establishing a diagnosis of Gilbert, Crigler-Najjar syndrome type I or type II

 

Establishing carrier status for Gilbert, Crigler-Najjar syndrome type I or type II

Method Name

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

Reporting Name

UGT1A1 Full Gene Sequencing

Specimen Type

Varies

Specimen Minimum Volume

Blood: 0.45 mL
Saliva: one swab

Specimen Stability Information

Specimen Type Temperature Time
Varies Varies

Reject Due To

Hemolysis

NA

Lipemia

NA

Icterus

NA

Other

NA

Clinical Information

The UGT1A1 gene is part of a gene complex located on chromosome 2 that encodes several enzymes called uridine diphosphate (UDP)-glycuronosyl transferases. These enzymes perform a chemical reaction called glucuronidation, a major pathway that enhances the elimination of small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble metabolites that can be excreted from the body.

 

The UGT1A1 enzyme, primarily found in the liver, is responsible for the gluronidation of bilirubin, converting it from the toxic form of bilirubin (unconjugated bilirubin) to its nontoxic, water-soluble form (conjugated bilirubin). Genetic variants in UGT1A1 may cause reduced or absent UGT1A1 enzymatic activity, resulting in conditions associated with unconjugated hyperbilirubinemia including Gilbert syndrome and Crigler-Najjar syndromes types I and II.

 

Gilbert syndrome is the most common hereditary cause of increased bilirubin and is characterized by total serum bilirubin levels of 1 to 6 mg/dL. Gilbert syndrome is generally considered to be an autosomal recessive disorder, although autosomal dominant inheritance has been suggested in some cases.(1) Gilbert syndrome is caused by a 25% to 50% reduction in glucuronidation activity of the UGT1A1 enzyme and is characterized by episodes of mild intermittent jaundice and the absence of liver disease.

 

Crigler-Najjar syndromes types I and II (CN1 and CN2) are autosomal recessive disorders caused by more severe reductions in UGT1A1 glucuronidation activity. CN1 is the most severe form, with complete absence of enzyme activity and total serum bilirubin levels of 20 to 45 mg/dL. Infants with CN1 present with jaundice shortly after birth that persists thereafter.(2) CN2 is milder than CN1, with at least partial UGT1A1 activity and total serum bilirubin ranging from 6 to 20 mg/dL. 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 CN2; CN1 does not respond to phenobarbital treatment. If left untreated, the buildup of bilirubin in a newborn can cause bilirubin-induced brain damage, known as kernicterus. In addition to phenobarbital, treatments of CN may include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation.

 

In addition to the role of UGT1A1 in bilirubin metabolism, this enzyme also plays a role in the metabolism of several drugs. UGT1A1 is involved in the metabolism of irinotecan, a topoisomerase I inhibitor. Irinotecan is a chemotherapy drug used to treat solid tumors including colon, rectal, and lung cancers. It is a prodrug that forms an active metabolite, SN-38. SN-38 is normally inactivated by conjugation with glucuronic acid followed by biliary excretion into the gastrointestinal tract. If UGT1A1 activity is impaired or deficient, SN-38 fails to become conjugated with glucuronic acid, increasing the concentration of SN-38. This can result in severe neutropenia. The combination of neutropenia with diarrhea can be life-threatening.(3,4)

 

Additional drugs have also been associated with an increased risk for adverse outcomes in patients with reduced UGT1A1 enzyme activity. 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 variants 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).

 

The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. In this assay, the promoter, exons, and exon-intron boundaries are assessed for variants.(5)

Reference Values

An interpretive report will be provided.

Interpretation

An interpretive report will be provided that includes assessment of risk for UGT1A1-associated adverse drug reactions as well as interpretation for hyperbilirubinemia syndromes.

 

For additional information regarding pharmacogenomic genes and their associated drugs, see the Pharmacogenomic Associations Tables in Special Instructions. This resource includes information regarding enzyme inhibitors and inducers, as well as potential alternate drug choices.

Clinical Reference

1. 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

2. 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

3. Goetz MP, Safgren S, Goldberg RM, et al: A phase I dose escalation study of irinotecan (CPT-11), oxaliplatin (Oxal), and capecitabine (Cap) within three UGT1A1 TA promoter cohorts (6/6, 6/7, and 7/7). ASCO 2005 ASCO Annual Meeting Abstract No: 2014

4. NDA 20-571/S-024/S-027/S-028. Camptosar (Irinotecan HCL) Final Label. July 21, 2005. Pfizer

5. 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

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

7. Gammal R, Court M, Haidar C, et al: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for UGT1A1 and Atazanavir Prescribing. Clin Pharm Ther 2015 doi: 10.1002/cpt.269

8. Shibata T, Minami Y, Mitsuma A, et al: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia. Int J Clin Oncol 2014;19:391-396

9. US Food and Drug Administration, Pharmacogenomic Biomarkers in Drug Labeling. Accessed November 2015. Available at www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

10. UDP-Glucuronosyltransferase Alleles Nomenclature page. Accessed March 2018. Available at www.pharmacogenomics.pha.ulaval.ca/ugt-alleles-nomenclature/

Day(s) and Time(s) Performed

Tuesday; 8 a.m.

Analytic Time

7 days (Not reported on Saturday or Sunday)

Performing Laboratory

Mayo Medical Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81479

LOINC Code Information

Test ID Test Order Name Order LOINC Value
UGTFG UGT1A1 Full Gene Sequencing In Process

 

Result ID Test Result Name Result LOINC Value
91972 Result Summary 50397-9
91977 TA Repeat Result In Process
BA0266 Full Gene Sequence Result In Process
91993 Interpretation In Process
92007 Additional Information 48767-8
92008 Method 49549-9
92009 Disclaimer 62364-5
92010 Reviewed By 18771-6

Testing Algorithm

See UGT1A1 Test Ordering Algorithm in Special Instructions.