Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome

Abstract

BackgroundInherited unconjugated hyperbilirubinemia is caused by variants in the gene UGT1A1 leading to Gilbert’s syndrome and Crigler-Najjar syndrome types I and II. These syndromes are differentiated on the basis of UGT1A1 residual enzymatic activity and its affected bilirubin levels and responsiveness to phenobarbital treatment.Case presentationIn this report, we present a boy with Crigler-Najjar syndrome type II with high unconjugated bilirubin levels that decreased after phenobarbital treatment but increased in adolescence. Four different UGT1A1 gene variants have been identified for this patient, of which one is novel (g.11895_11898del) most likely confirming diagnose molecularly.ConclusionsThe presented case highlights the challenges encountered with the interpretation of molecular data upon identification of multiple variants in one gene that are causing different degree reducing effect on enzyme activity leading to several clinical conditions.

UGT1A1 Variants c.864+5G>T and c.996+2_996+5del of a Crigler-Najjar Patient Induce Aberrant Splicing in Minigene Assays

“…Our Crigler-Najjar syndrome type II patient with 29.6% expression of the canonical transcript from one allele (c.864+5G>T) does not appear to fulfill this criterion. Also family segregation data from our previous study suggested that each of the variants separately did not reduce UGT1A1 enzyme activity enough to cause Crigler-Najjar syndrome type II (Gailite et al, 2018). However, there are two possible explanations as to why in vivo expression could be even more reduced.…”

“…We previously identified two putative variants that affected the canonical donor splice sites of UGT1A1 exons 1 and 2 (Gailite et al, 2018). Both variants were predicted by MES to disrupt their respective splice site.…”

“…The DNA of a patient with unconjugated hyperbilirubinemia was isolated from peripheral blood and the UGT1A1 gene was sequenced as described previously (Gailite et al, 2018). Four different genetic variants were identified.…”

“…We have previously detailed a patient with clinically diagnosed Crigler-Najjar syndrome type II caused by multiple allelic variants in the UGT1A1 gene (Gailite et al, 2018). One of these variants was a novel deletion of four intronic nucleotides after exon 2 (NG_033238.1:g.11895_11898del, c.996+2_996+5del), potentially affecting the donor splice site.…”

“…Another one was a nucleotide substitution in the +5 position of the first exonintron splice junction (NG_033238.1:g.5884G>T, c. 864+5G>T, rs777807265). Both variants were in trans and affected the 5 splice sites; however, the absence of functional studies limited their clinical interpretations (Gailite et al, 2018). Interestingly, more than two decades ago, splice site variants were first proposed as a possible cause of unconjugated hyperbilirubinemia (Gantla et al, 1998).…”