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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 (de novo) inheritance in the children. Pathogenicity of the variants was predicted with an in-house developed algorithm (GAVIN). Secondly, we performed a cohort analysis in which we prioritised genes that carried a rare pathogenic variant in 3 or more cases, but were not found in population controls.


We identified compound heterozygous variants in three trios in genes ABCB6, DACT1 and JMJDC1, and in 13 other trios we identified a total of 16 de novo variants in 16 genes with predicted pathogenic effects on protein functions. The same de novo CNOT2 variant was shared between two families, as well as the de novo TNRC18 variant. Most identified genes have roles in bile salt transport and the immune system.


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.