Gilbert's syndrome (Meulengracht's juvenile jaundice, benign intermittent jaundice) is an autosomal recessive disease characterised by a benign indirect hyperbilirubinemia with intermittent symptoms of jaundice. It manifests by a chronic increase of unconjugated bilirubin levels in serum without the presence of bilirubin in urine, without hyperhemolysis and without other signs of liver disease. Its incidence in indo-european population is 3 - 15 % (in ČR 5 %).
GS is caused by decreased activity of the UDP-glucuronyl transferase A1 enzyme which is encoded by the UGT 1A1 gene.
UGT 1A1 gene is located in the region 2q37 (contains 5 exons and has the size of 218 kb).
The most frequent cause of Gilbert's syndrome (more than 90 %) is the insertion of TA sequece in the TATA box in the promoter site of the UGT 1A1 gene. Normal ("wild type") promoter contains 6 TA repetitive sequences (6TA/6TA) while in the affected persons increases to 7. This limits the recognition of promoter region by transcription factors and so decreases the expression of UGT 1A1 gene. In a heterozygous form (6TA/7TA ), from the physiological viewpoint, it comes to "subliminal effect" whereas in mutated homozygotes with an insertion in both alleles (7TA/7TA) it comes to decreasing of the UDP-glucuronyl transferase activity of about 20 -30 %, which is no longer sufficient to cover the metabolic processes.
Complications in the condition (leucopenia and diarrhea) may occur among oncology patients who are treated by irinotecan (medication CAMPTO) and who are also homozygous (7TA/7TA) or heterozygous (6TA/7TA). Therefore, it is reccomended to examine the patient for the presence of TA insertion in the UGT promoter of the 1A1 gene.
In our laboratory, we perform the detection of the number of TA insertion by fragmentation analysis of PCR products on the ABI PRISM 3130xl genetic analyzer using the GeneMapper program. Diagnosis is confirmed in the case of 7TA/7TA genotype. In other cases (6TA/7TA or 6TA/6TA genotypes), it is possible to perform the mutation analysis of the whole UGT 1A1 gene by direct sequencing assuming that the clinical symptoms and biochemical values fulfill the criteria of Gilbert's syndrome.
The cause of the disease Gilbert's syndrome is an alteration of the gene UGT1A1. It is found the most (> 90%), insertion of dinucleotide sequence TA in the TATA box in the promoter region of the gene UGT1A1.
Sequence analysis of the coding exons and exon-intron connections detects about 96% of mutations in the UGT1A1 listed in a publicly available version of the mutation database HGMD (The Human Gene Mutation Database).
Analytical sensitivity and specificity of the sequencing: 99%.
Mutations deep in the introns and regulatory sequences are not detected. Rare polymorphisms in the location of annealing primers may cause a diagnostic error.