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Keywords:

  • Bilirubin;
  • Crigler–Najjar syndrome;
  • Gilbert syndrome;
  • consanguineous;
  • novel mutations

Summary

Two inherited unconjugated hyperbilirubinemias, Crigler–Najjar syndrome and Gilbert syndrome, arise due to deficiency of UGT1A1 enzyme activity. Crigler–Najjar syndrome type 1 (CN1) lies at the extreme severe end of the spectrum of UGT1A1 activity characterized by complete absence, followed by the less severe Crigler–Najjar syndrome type 2 (CN2). Gilbert syndrome is the mild form having only partial loss of UGT1A1 activity. The present study aimed to identify molecular genetic defects underlying unconjugated hyperbilirubinemias in children from six consanguineous Pakistani families. The patients were clinically diagnosed by exclusion of other unconjugated hyperbilirubinemias. Differential diagnosis of CN1 and CN2 was made on the basis of patient's response to phenobarbitone. The promoter region, coding exons, and adjacent splice sites of the UGT1A1 gene were PCR amplified from genomic DNA of all patients and their families, and were sequenced. DNA sequence analysis identified five different homozygous mutations: two novel missense mutations p.Y230C (proband A) and p.D36N (proband B), a 4-bp insertion c.622–625dupCAGC/p.Q208QfsX50 (probands C and E), a nonsense mutation p.R341X (proband D), and a TA insertion A(TA)7TAA in the promoter region (proband F). The present study extends the spectrum of UGT1A1 gene mutations and may be helpful in the diagnosis of Crigler–Najjar syndrome and Gilbert syndrome.