Spectrum of UGT1A1 variants in Pakistani children affected with inherited unconjugated hyperbilirubinemias.

Inherited unconjugated hyperbilirubinemias are a group of disorders characterized by increased levels of serum unconjugated bilirubin and arise because of the imbalance between its production and elimination from the body. It includes Crigler-Najjar syndrome and Gilbert syndrome. Crigler-Najjar syndrome type 1 represents the extreme severe end of the spectrum with complete absence of hepatic bilirubin uridine diphosphoglucuronate glucuronosyltransferase (UGT1A1). Crigler-Najjar syndrome type 2 patients have intermediate levels of bilirubin owing to incomplete deficiency of UGT1A1, and Gilbert syndrome lies at the extreme mild end of the spectrum with only slightly raised bilirubin level. Here, we present spectrum of UGT1A1 genetic variants in 25 Pakistani children from 23 unrelated families affected with persistent unconjugated hyperbilirubinemias. The promoter region, coding exons and splice junctions of the UGT1A1 were PCR amplified and subjected to Sanger sequencing. Eleven sequence variants were identified underlying disease phenotype including a novel c.582delC variant. Overall, c.622_625dupCAGC was the most frequent variant followed by c.1021C>T found in Crigler-Najjar syndrome type 1 patients. The evaluation of promoter polymorphism A(TA)TAA in the affected children and their families further supported the body of evidence that the A(TA)TAA allele could enhance the effect of other structural variants in Crigler-Najjar syndrome patients. To our knowledge, this is the first comprehensive study on molecular genetics of persistent unconjugated hyperbilirubinemias from Pakistan. This study expands the spectrum of UGT1A1 variants and should help in improved clinical diagnosis, genetic counseling and prenatal diagnosis of the affected families.