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)nTAA in the affected children and their families further supported the body of evidence that the A(TA)7TAA 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.