Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes

Wong, J. K. L. et al. (2016) Genetic study of congenital bile-duct dilatation identifies de novo and inherited variants in functionally related genes. BMC Medical Genomics, 9(1), 75. (doi: 10.1186/s12920-016-0236-z) (PMID:27955658) (PMCID:PMC5154011)

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Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Campbell, Dr Desmond
Authors: Wong, J. K. L., Campbell, D., Ngo, N. D., Yeung, F., Cheng, G., Tang, C. S. M., Chung, P. H. Y., Tran, N. S., So, M.-t., Cherny, S. S., Sham, P. C., Tam, P. K., and Garcia-Barcelo, M.-M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:BMC Medical Genomics
Publisher:BioMed Central
ISSN (Online):1755-8794
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in BMC Medical Genomics 9(1):75
Publisher Policy:Reproduced under a Creative Commons License

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