AB113. The first genetic study on congenital choledochal dilatation (CCD) implicates extracellular matrix proteins

Abstract: Congenital choledochal dilatation (CCD) or paediatric choledochal cyst refers to the congenital dilatation of the choledochs (bile ducts) which leads to the obstruction of the ducts and bile retention. Symptoms include cholestatic jaundice, abdominal pain and liver enlargement complicated with cholangitis and pancreatitis. New-borns undergo surgery otherwise the liver could be permanently damaged. CCD is rare, mostly sporadic with variable population incidence, the highest being in Asia (1/1,000 in Asians; 1/150,000 in Caucasians). Its aetiology implicates congenital structural anomalies reflecting a failure in the hepatobiliary-pancreatic development. Thirty-one CCD trios were exome sequenced. Gene/pathway-set enrichment analyses grouped genes with at least one damaging allele into focal adhesion and extracellular matrix-receptor interaction pathways. Pathogenic mechanisms considered included de novo germ-line mutations and/or recessive inherited mutations in homozygosis, compound heterozygosis (CH) or as “di-genic/oligogenic” model of inheritance whereby variants in genes of related pathways coexist in a patient through parental inheritance. Fifteen gene members of those pathways were recurrently mutated and had variants at different sites (more than one damaging allele per gene). These alleles were in CH or co-existing with a mutated functional gene-partner in the same individual. Patients’ genetic profiling revealed CCD as not only genetically heterogeneous but with di/oligogenic inheritance. Yet, the relevant mutated genes are functionally convergent. Data are consistent with the sporadic presentation of CCD. Incidentally, the cholangiocarcinoma rate in Asians is also the highest world-wide. We are also aiming at finding possible links between these choledochal disorders and at explaining their high incidence in Asia.

Keywords: Congenital choledochal dilatation (CCD); exome sequencing