P819 Whole-exome sequencing in early-onset primary sclerosing cholangitis: first results of the WHELP study
S-M. Haisma*1, R. Weersma2, M. Joosse3, B. de Koning3, T. de Meij4, B. Koot5, V. Wolters6, O. Norbruis7, M. Daly8, C. Stevens8, R. Xavier9, M. Rivas10, R. Barbieri2, D. Jansen2, N. Festen2, H. Verkade1, M. Visschedijk2, C. van Diemen11
1University Medical Center Groningen, Paediatric Gastroenterology, Groningen, The Netherlands, 2University Medical Center Groningen, Gastroenterology and Hepatology, Groningen, The Netherlands, 3Erasmus University Medical Center, Paediatric Gastroenterology, Rotterdam, The Netherlands, 4VU University Medical Center, Paediatric Gastroenterology, Amsterdam, The Netherlands, 5Emma Children's Hospital - Amsterdam UMC, Paediatric Gastroenterology, Amsterdam, The Netherlands, 6University Medical Center Utrecht, Paediatric Gastroenterology, Utrecht, The Netherlands, 7Isala Hospital, Paediatrics, Zwolle, The Netherlands, 8Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, USA, 9Massachusetts General Hospital, Gastroenterology, Boston, USA, 10Stanford University, Stanford, USA, 11University Medical Center Groningen, Genetics, Groningen, The Netherlands
Primary sclerosing cholangitis (PSC) is a severe liver disease leading to fibrotic destruction of the bile ducts and ultimately to the need for liver transplantation. In children the connection with inflammatory bowel disease (IBD) is close to 100%. Genome-wide association studies (GWAS) in adults have identified many risk loci for both IBD and PSC, but a large part of the heritability remains unexplained. We hypothesise that we can identify rare, but disease-causing variants in patients with an extreme PSC phenotype, such as children with early-onset PSC.
In this multi-centre parent-offspring study, we collected DNA from 31 children who were diagnosed with PSC before the age of 13, and their biological parents. Whole-exome sequencing (WES) was performed on all 93 DNA samples. We first performed parents-child trio analyses and prioritised rare coding and splice variants matching recessive (homozygous and compound heterozygous variants) and dominant (
We identified compound heterozygous variants in three trios in genes
So far, 19 candidate disease-causing variants with large effects on protein function were found in children with early-onset PSC involving immunological or bile salt pathways. Network analysis is currently being performed to assess the relation between these genes and signalling pathways associated with PSC and or IBD.