UDP-Glucuronosyl Transferase 1A1 (UGT1A1) Gene, Known Mutation
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Bilirubin, resulting from the breakdown of heme, is a water-insoluble toxic compound. Uridine diphosphate (UDP)-glucuronosyl 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 mutations in the UGT1A1 gene may cause reduced or absent UGT1A1 enzymatic activity resulting in hyperbilirubinemia (eg, Gilbert syndrome, Crigler-Najjar syndrome).
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) types I and II are inherited causes of severe unconjugated hyperbilirubinemia. CN type I is associated with no UGT1A1 enzymatic activity and usually presents as intense jaundice in the first days of life and persists thereafter.(3) Type II is a milder form in which bilirubin levels are <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 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, bilirubin-induced brain damage. Treatments of CN include: phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, and liver transplantation. Phototherapy becomes ineffective at later ages and liver transplantation should occur prior to the onset of brain damage (before phototherapy becomes ineffective).
The UGT1A1 gene maps to chromosome 2q37 and contains 5 exons. Currently, there are more than 130 known mutations in UGT1A1, with 45 mutations that cause a decrease in UGT1A1 enzyme activity. Analysis is performed for the familial mutation only.
Identifying the presence of a UGT1A1 mutation when the mutation has been identified in a family member (carrier or affected)
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
UGT1A1 genetic test results in patients who have undergone liver transplantation may not accurately reflect the patient’s UGT1A1 status.
This test is for individuals who are at risk for a UGT1A1 mutation that has been previously identified in the family. If the familial mutation is not known, the familial proband should be screened for a UGT1A1 mutation using UGT2 / UDP-Glucuronosyl Transferase 1A1 (UGT1A1), Full Gene Sequencing, Hyperbilirubinemia.
This assay does not rule out the presence of other mutations within this gene. This test can only be used for known mutations occurring in the promoter, exons, exon-intro boundaries, and the region in the distal promoter called the "phenobarbital response enhancer module."
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.
Rare polymorphisms 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.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
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