title: Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes.
abstract: Congenital dilatation of the bile-duct (CDD) is a rare, mostly sporadic, disorder that results in bile retention with severe associated complications. CDD affects mainly Asians. To our knowledge, no genetic study has ever been conducted.
  
  
  
  We aim to identify genetic risk factors by a "trio-based" exome-sequencing approach, whereby 31 CDD probands and their unaffected parents were exome-sequenced. Seven-hundred controls from the local population were used to detect gene-sets significantly enriched with rare variants in CDD patients.
  
  
  
  Twenty-one predicted damaging de novo variants (DNVs; 4 protein truncating and 17 missense) were identified in several evolutionarily constrained genes (p < 0.01). Six genes carrying DNVs were associated with human developmental disorders involving epithelial, connective or bone morphologies (PXDN, RTEL1, ANKRD11, MAP2K1, CYLD, ACAN) and four linked with cholangio- and hepatocellular carcinomas (PIK3CA, TLN1 CYLD, MAP2K1). Importantly, CDD patients have an excess of DNVs in cancer-related genes (p < 0.025). Thirteen genes were recurrently mutated at different sites, forming compound heterozygotes or functionally related complexes within patients.
  
  
  
  Our data supports a strong genetic basis for CDD and show that CDD is not only genetically heterogeneous but also non-monogenic, requiring mutations in more than one genes for the disease to develop. The data is consistent with the rarity and sporadic presentation of CDD.
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1F Room 5D HKJCBIR, 5 Sassoon Road, Hong Kong, SAR, China.
authors.forename: John K L
authors.initials: JK
authors.lastname: Wong
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1F Room 5D HKJCBIR, 5 Sassoon Road, Hong Kong, SAR, China.
authors.forename: Desmond
authors.initials: D
authors.lastname: Campbell
authors.affiliation: National Hospital of Pediatrics, Hanoi, Vietnam.
authors.forename: Ngoc Diem
authors.initials: ND
authors.lastname: Ngo
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Fanny
authors.initials: F
authors.lastname: Yeung
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Clara S M
authors.initials: CS
authors.lastname: Tang
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Patrick H Y
authors.initials: PH
authors.lastname: Chung
authors.affiliation: National Hospital of Pediatrics, Hanoi, Vietnam.
authors.forename: Ngoc Son
authors.initials: NS
authors.lastname: Tran
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1F Room 5D HKJCBIR, 5 Sassoon Road, Hong Kong, SAR, China.|Center for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.affiliation: Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 1F Room 5D HKJCBIR, 5 Sassoon Road, Hong Kong, SAR, China.|Center for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Pak C
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Tam
authors.affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China. mmgarcia@hku.hk.|Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China. mmgarcia@hku.hk.
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barcelo
mesh_terms: D015529:Choledochal Cyst / Q000235:genetics*; D019295:Computational Biology; D019143:Evolution, Molecular; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation
keywords: Choledochal cyst; De novo; Exome; Rare variants association