UGT1A1 Sequencing

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.