Abstract
Aim: Single gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in approximately two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized that children with idiopathic cholestasis have a higher frequency of heterozygous non-synonymous gene sequence variants. Methods: We analyzed the frequency and types of variants in 717 children in whom high-throughput sequencing of the genes SERPINA1, JAG1, ATP8B1, ABCB11 and ABCB4 was performed as part of an evaluation for idiopathic intrahepatic cholestasis cholestasis. The frequency of non-synonymous variants (NSV) was compared with those of 1092 control subjects enrolled in the 1000 Genome Project. Results: The frequency of NSV in single genes was similar between disease (25%) and controls (26%, P=0.518). In contrast, double or triple NSV in two or more genes were more frequent in disease (n=7%) than controls (n=4.7%, P=0.028). Detailed review of clinical and laboratory information in a subgroup of double or triple heterozygous patients revealed variable γ-glutamyltransferase levels and severity of pruritus, with liver biopsies showing stage 2-3 fibrosis. Conclusion: Children with idiopathic intrahepatic cholestasis have a higher frequency of double or triple NSV in SERPINA1, JAG1, ATPB1, ABCB11 or ABCB4. These findings raise the potential role for gene-gene relationships in determining the phenotype of cholestatic liver disease in children.
Original language | English (US) |
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Pages (from-to) | 306-311 |
Number of pages | 6 |
Journal | Hepatology Research |
Volume | 46 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2016 |
Externally published | Yes |
Keywords
- Children
- Cirrhosis
- Jaundice
- Liver
- Mutations
ASJC Scopus subject areas
- Hepatology
- Infectious Diseases