Gilbert syndrome - Gene UGT1A1

Gilbert syndrome, also called hyperbilirubinemia 1, is a condition characterized by periods of hyperbilirubinemia. Bilirubin is removed from the body only after the toxic form of bilirubin (unconjugated bilirubin) is converted into a nontoxic form called conjugated bilirubin.

Gilbert syndrome is usually recognized in adolescence. Approximately 30 % of affected people does not present symptoms, although the affected individuals can manifest a mild jaundice under stress situations, for instance under dehydration, fasting, illness, vigorous exercise, or menstruation. Other signs and symptoms may include abdominal discomfort or tiredness.

This process is due to mutations in the UGT1A1 (UDP glucuronosyltransferase family 1 member A1) gene, located in the long arm of chromosome 2 (2q37.1). This gene provides instructions for making the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme, which is found primarily in liver cells and is necessary for the removal of bilirubin from the body. The bilirubin-UGT enzyme performs a chemical reaction called glucuronidation. During this reaction, the enzyme transfers glucuronic acid to unconjugated bilirubin, converting it to conjugated bilirubin. Glucuronidation makes bilirubin soluble in water so that it can be removed from the body.

The most common genetic change that causes Gilbert syndrome (UGT1A1*28) occurs in the promoter region, which controls the production of the bilirubin-UGT enzyme. This genetic change impairs enzyme production. Affected Asians often have a missense mutation that changes a amino acid in the bilirubin-UGT enzyme, resulting in a reduced enzyme function. As a result, unconjugated bilirubin is not glucuronidated quickly enough. This toxic substance then builds up in the body, causing mild hyperbilirubinemia.

Gilbert syndrome can have different inheritance patterns. When is caused by the UGT1A1*28 change in the promoter region of the UGT1A1 gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have the mutation. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. When Gilbert syndrome  is caused by a missense mutation in the UGT1A1 gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is enough to cause the disorder. A more severe condition known as Crigler-Najjar syndrome occurs when both copies of the UGT1A1 gene have mutations.

Tests performed in IVAMI: We performed the detection of mutations associated with Gilbert syndrome, through the complete PCR amplification of exons of the UGT1A1 gene, and its subsequent sequencing.

Recommended samples: blood extracted with EDTA for separation of blood leucocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).