26622 UDP-Glucuronosyltransferase 1A1 (UGT1A1), Full Gene Sequencing, Varies (UGTFZ)

​Atazanavir; Belinostat; Crigler-Najjar Syndrome; Gilbert Syndrome; Hyperbilirubinemia; Irinotecan; Irinotecan glucuronidation; Irinotecan metabolism; Nilotinib; Pazopanib; Phenol/Bilirubin; Sacituzumab govitecan; UDP-Glucosyltransferase 1; UDP-Glucuronosyltransferase; UGT1A1; Uracil Glucuronyl transferase; Uridine Diphosphate Glucosyltransferase 1​​

​This test screens for UGT1A1 gene sequence variants associated with increased risk of adverse drug reactions when taking UGT1A1-metabolized drugs. These drugs include atazanavir, belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab govitecan. In addition, sequence variants may impact drug levels for patients taking dolutegravir or raltegravir.

This test screens for UGT1A1 gene sequence variants associated with congenital hyperbilirubinemia conditions, including Gilbert syndrome, Crigler-Najjar syndrome type I and type II.

​Establishing a diagnosis of Crigler-Najjar syndrome type I or type II and the trait of Gilbert syndrome

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

Identifying individuals who are at risk of hyperbilirubinemia or who have Gilbert syndrome

Identifying individuals who are at increased risk of adverse drug reactions or hyperbilirubinemia when taking drugs that are metabolized by UGT1A1, including atazanavir, belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab govitecan

Identifying individuals who may have increased drug levels when taking dolutegravir or raltegravir

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

​Patient Preparation: A previous hematopoietic stem cell transplant from an allogenic donor or a liver transplant will interfere with testing. For information about testing patients who have received a hematopoietic stem cell or liver transplant, call 800-533-1710.

Specimen Type: Whole Blood

Collection Instructions:
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.

Additional Information:

1. Specimens are preferred to be received within 4 days of collection. Extraction will be attempted for specimens received after 4 days, and DNA yield will be evaluated to determine if testing may proceed.

2. To ensure minimum volume and concentration of DNA are met, the requested volume must be submitted. Testing may be canceled if DNA requirements are inadequate.

3. For postnatal umbilical cord whole blood specimens, maternal cell contamination studies are recommended to ensure test results reflect that of the patient tested. A maternal blood specimen is required to complete maternal cell contamination studies. Order MATCC / Maternal Cell Contamination, Molecular Analysis, Varies on both the cord blood and maternal blood specimens under separate order numbers.

NOTE:  For cord blood specimens that have an accompanying maternal blood specimen, maternal cell contamination studies will be performed at an additional charge (Test ID:  MATCC (Maternal Cell Contamination, B).​

Specimen Type:  Saliva

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

Collection Instructions:
Collect and send specimen per kit instructions.  (DNA Saliva Kit High Yield (T1007); Saliva Swab Collection Kit (T786)).

Collect 1 Tube if using T1007 or 2 swabs if using T786.

NOTE: Saliva specimens are acceptable but not recommended. Due to lower quantity/quality of DNA yielded from saliva, some aspects of the test may not perform as well as DNA extracted from a whole blood sample. When applicable, specific gene regions that were unable to be interrogated will be noted in the report. Alternatively, additional specimen may be required to complete testing.

All specimens will be evaluated at Mayo Clinic Laboratories for test suitability. ​

​Clinical Correlations:

If the patient has had an allogeneic hematopoietic stem cell transplant (bone marrow transplant) or a recent non-leukocyte reduced blood transfusion, results may be inaccurate due to the presence of donor DNA. For individuals who have received allogeneic hematopoietic stem cell 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. Contact Mayo Clinic Laboratories for information and guidance when testing patients who have received a transplant. Absence of a detectable gene variant does not rule out the possibility that the patient may have a genetic cause for increased unconjugated bilirubin.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact Mayo Clinic Laboratories genetic counselors at 800-533-1710.

Technical Limitations:
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.

Reclassification of Variants:
Currently, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time.

Variant Evaluation:
Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline. Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools are interpreted with caution and professional clinical judgment.

​​The UGT1A1 gene contains 5 exons and is part of a gene complex located on chromosome 2q37 that encodes several enzymes called uridine diphosphate (UDP)-glucuronosyltransferases. 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 glucuronidation 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 syndrome.

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 trait, although autosomal dominant inheritance has been suggested in some cases. Gilbert syndrome is characterized by a 25% to 50% reduction in glucuronidation activity of the UGT1A1 enzyme, along with episodes of mild intermittent jaundice and the absence of liver disease.

Crigler-Najjar (CN) syndrome is an autosomal recessive disorder caused by more severe reductions in UGT1A1 glucuronidation activity and can be subdivided into type 1 and type 2 (CN1 and CN2). CN1 is the most severe form, with complete absence of enzyme activity and total serum bilirubin levels of 20 to 40 mg/dL. Infants with CN1 present with jaundice shortly after birth that persists thereafter. 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 drug metabolism. 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 and diarrhea, which can be life-threatening.

Additional drugs have also been associated with an increased risk for adverse outcomes in patients with reduced UGT1A1 enzyme activity. The US Food and Drug Administration drug labels for belinostat, nilotinib, pazopanib, and sacituzumab govitecan contain warnings for an increased risk (incidence) of adverse outcomes or increased bilirubin 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). Additionally, the concentration of several drugs, including dolutegravir and raltegravir, may be increased in patients with reduced UGT1A1 enzyme activity.

In this assay, the UGT1A1 promoter, exons, and exon-intron boundaries are assessed for variants.

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

All detected variants are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

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