Crigler-Najjar Syndrome and Gilbert Syndrome via the UGT1A1 Gene

Defects in the UGT1A1 gene can cause both type I and II Crigler-Najjar syndrome (CN1 and CN2) characterized by non-hemolytic unconjugated hyperbilirubinemia (excessive bilirubin in the blood) (Bosma et al. 1992. PubMed ID: 1568736; Ritter et al. 1992. PubMed ID: 1634606; Seppen et al. 1994. PubMed ID: 7989595). Hyperbilirubinemia can cause jaundice (yellowing of the skin and whites of the eyes) and lead to kernicterus (brain damage caused by the accumulation of unconjugated bilirubin in the brain and nerve tissues). In Crigler-Najjar syndrome, jaundice is apparent at birth or in infancy. CN1 is the most severe form with absence of hepatic bilirubin-uridinediphosphoglucuronate (UDP) glucuronosyltransferase (encoded by UGT1A1) activity. CN2 presents with intermediate levels of hyperbilirubinaemia, resulting in an incomplete deficiency of hepatic UGT1A1 activity. UGT1A1 defects can also cause the more common mild hyperbilirubinemia known as Gilbert syndrome (Koiwai et al. 1995. PubMed ID: 8528206; Kadakol et al. 2000. PubMed ID: 11013440), depending on the degree of deficiency of the UDP-glycuronosyltransferase.

Several common polymorphisms in UGT1A1, including the A(TA)7AA allele, have been linked to indirect hyperbilirubinemia with jaundice resulting from adverse drug reactions (for more information, please review Gammal et al. 2016. PubMed ID: 26417955; https://www.pharmgkb.org/gene/PA420). However, this sequencing test has been designed for the molecular diagnosis of patients who present with inherited Crigler-Najjar syndrome or Gilbert syndrome and is not meant to be a pharmacogenetic analysis for this gene, nor has it been designed to help guide dosage requirements. Several common polymorphisms that may affect drug response may not be reported out as part of this test.

Crigler-Najjar syndrome types I and II are autosomal recessive disorders caused by defects in the UGT1A1 gene (Bosma et al. 1992. PubMed ID: 1568736; Ritter et al. 1992. PubMed ID: 1634606; Seppen et al. 1994. PubMed ID: 7989595). Gilbert syndrome is generally considered to be an autosomal recessive disorder, but autosomal dominant inheritance has also been suggested (Koiwai et al. 1995. PubMed ID: 8528206; Kadakol et al. 2000. PubMed ID: 11013440). UGT1A1 has five coding exons that encode the UDP-glycuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules such as bilirubin into water-soluble and excretable metabolites. Genetic defects of UGT1A1 include missense, nonsense, splicing variants and small frameshift deletion/insertions (Human Gene Mutation Database). Exon-level large deletions involving UGT1A1 have been also reported, but are uncommon.

The detection rate of UGT1A1 pathogenic variants in a cohort of patients with Crigler-Najjar syndrome type I and II or Gilbert syndrome is unknown as only individual cases have been reported.

It is difficult to estimate the exact clinical sensitivity of CNV detection due to the lack of large cohort studies. Large deletions in the UGT1A1 gene have been previously reported, but are uncommon (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the UGT1A1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

The well-known A(TA)nTAA region of the UGT1A1 promoter is also covered in this test.

Several common polymorphisms in UGT1A1, including the A(TA)7AA allele, have been linked to indirect hyperbilirubinemia with jaundice resulting from adverse drug reactions (for more information, please review Gammal et al. 2016. PubMed ID: 26417955; https://www.pharmgkb.org/gene/PA420). However, this sequencing test has been designed for the molecular diagnosis of patients who present with inherited Crigler-Najjar syndrome or Gilbert syndrome and is not meant to be a pharmacogenetic analysis for this gene, nor has it been designed to help guide dosage requirements. Several common polymorphisms that may affect drug response may not be reported out as part of this test.