Ordering Recommendation

Preferred test to confirm diagnosis of Gilbert (benign familial hyperbilirubinemia) or Crigler-Najjar syndrome. May be used when prescribing atazanavir to assess likelihood of bilirubin-related discontinuation. May also be useful in dosage planning for individuals who will receive high-dose irinotecan or experience neutropenia while receiving irinotecan.

Mnemonic
UGT1A1 FGS
Methodology

Polymerase Chain Reaction/ Sequencing

Performed

Sun-Sat

Reported

2-3 weeks

New York DOH Approval Status
Specimens from New York clients will be sent out to a New York DOH approved laboratory, if possible.
Specimen Required
Patient Preparation
Collect

Lavender (K EDTA), Pink (K EDTA), or Yellow (ACD Solution A or B).

Specimen Preparation

Transport 3 mL whole blood. (Min: 1 mL)

Storage/Transport Temperature

Refrigerated

Unacceptable Conditions
Remarks
Stability

Ambient: 1 week; Refrigerated: 1 month; Frozen: 6 months

Reference Interval
Interpretive Data

Background Information for UGT1A1 Sequencing:
Characteristics:
UGT1A1 encodes the bilirubin uridine diphosphate glucuronosyl transferase 1A1 enzyme, which is responsible for the clearance of drugs (eg, irinotecan) and endogenous compounds (eg, bilirubin). UGT1A1 deficiency is associated with inherited nonhemolytic unconjugated hyperbilirubinemia and a spectrum of phenotypes dependent on the level of residual enzyme activity. Crigler-Najjar syndrome type I, results from absent enzyme activity and severe unconjugated hyperbilirubinemia causing jaundice and risk for kernicterus. Crigler-Najjar syndrome type II, is associated with reduced hepatic enzyme activity, intermediate levels of hyperbilirubinemia, and low risk for kernicterus. Gilbert syndrome is clinically benign and associated with mild, fluctuating hyperbilirubinemia, which can be caused by impaired bilirubin glucuronidation. Pathogenic UGT1A1 variants are also associated with an increased risk for irinotecan toxicity (neutropenia and diarrhea) and bilirubin-related discontinuation of atazanavir.
Cause:
Two pathogenic UGT1A1 variants on opposite chromosomes. A variable number of TA repeats in the (TA)nTAA element of the UGT1A1 promoter affects transcription efficiency. The common number of repeats is six (TA)6, *1 allele, while seven repeats (TA)7, *28 allele is associated with reduced transcription activity.
Epidemiology:
Incidence of Crigler-Najjar syndrome is estimated at 1 in 1 million newborns worldwide. Approximately 3-7 percent of individuals in the U.S. have Gilbert syndrome.
Inheritance: Autosomal recessive for Crigler-Najjar and Gilbert syndromes.
Clinical Sensitivity/Specificity: Unknown for Crigler-Najjar and Gilbert syndromes. Estimated risk of irinotecan toxicity by genotype in Caucasian patients with colorectal cancer (PMID: 23529007).
  (TA)6/6 (*1/*1): diarrhea 15 percent; neutropenia 11 percent.
  (TA)6/7 (*1/*28): diarrhea OR=1.20; neutropenia OR=1.90.
  (TA)7/7 (*28/*28): diarrhea OR=1.84; neutropenia OR=4.79.
Risks for bilirubin-related atazanavir discontinuation by predicted UGT1A1 phenotype (PMID: 26417955):
  Poor metabolizer (*28/*28, *28/*37, *37/*37): 20-60 percent.
  Intermediate metabolizer (*1/*28, *1/*37, *36/*28, *36/*37): less than 5 percent.
  Extensive or normal metabolizer (*1/*1, *1/*36, *36/*36): less than 5 percent.
Methodology: Bidirectional sequencing of the UGT1A1 coding regions, intron/exon boundaries, and polymorphic (TA)nTAA repeat within the promoter region.
Analytical Sensitivity:
Greater than 99 percent.
Limitations:
Diagnostic errors can occur due to rare sequence variations. UGT1A1 regulatory region variants other than the (TA)nTAA promoter variant will not be analyzed. Deep intronic variants, large deletions/duplications/insertions, and gene conversion events will not be detected. Variants of uncertain clinical significance within the UGT1A1 coding region will not be reported for pharmacogenetic indications. Genetic and non-genetic factors other than UGT1A1, may contribute to irinotecan toxicity and efficacy.

Compliance Statement C: For human genetic inheritable conditions and mutations. This test was developed and its performance characteristics determined by ARUP Laboratories. The U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use. The results are not intended to be used as the sole means for clinical diagnosis or patient management decisions.

Counseling and informed consent are recommended for genetic testing. Consent forms are available online.

Note
Hotline History
N/A
CPT Codes

81479

Components
Component Test Code* Component Chart Name LOINC
3001756 Specimen UGT1A1 FGS 31208-2
3001757 UGT1A1 FGS Interpretation 34509-0
* Component test codes cannot be used to order tests. The information provided here is not sufficient for interface builds; for a complete test mix, please click the sidebar link to access the Interface Map.
Aliases
  • atazanavir
  • bilirubin uridine diphosphate glucuronosyl transferase 1A1 enzyme
  • hyperbilirubinemia
  • Irinotecan toxicity
  • pharmacogenetics
  • pharmacogenomics
UGT1A1 Sequencing