Abstract
Hirschsprung disease (HSCR) is a complex birth defect characterized by the lack of ganglion cells along a variable length of the distal intestine. A large proportion of HSCR patients remain genetically unexplained. We applied whole-genome sequencing (WGS) on 9 trios where the probands are sporadically affected with the most severe form of the disorder and harbor no coding sequence variants affecting the function of known HSCR genes. We found de novo protein-altering variants in three intolerant to change genes—CCT2, VASH1, and CYP26A1—for which a plausible link with the enteric nervous system (ENS) exists. De novo single-nucleotide and indel variants were present in introns and non-coding neighboring regions of ENS-related genes, including NRG1 and ERBB4. Joint analysis with those inherited rare variants found under recessive and/or digenic models revealed both patient-unique and shared genetic features where rare variants were found to be enriched in the extracellular matrix–receptor (ECM–receptor) pathway (p = 3.4 × 10−11). Delineation of the genetic profile of each patient might help finding common grounds that could lead to the discovery of shared molecules that could be used as drug targets for the currently ongoing cell therapy effort which aims at providing an alternative to the surgical treatment.
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Acknowledgements
We are grateful to the numerous patients, their families and referring physicians that have participated in these studies in our laboratories, and the numerous members of our laboratories for their valuable contributions over many years.
Funding
This work was supported by: Theme-based Research scheme T12C-714/14-R to P.T., Human Medical Research Fund (HMRF) 02131866 and 01121516 to M.M.G.B and 0451966 to C.S.T. and Seed Fund for Basic Research of the University of Hong Kong 201606159005 to C.S.T.
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M.-M.G.-B., P.C.S., and P.K.T. conceived the experiments. C.S.T., X.Z. and M.-M.G.-B. wrote the article. P.C.S. and S.S.C. contributed to critical revision of the article. C.S.T. and X.Z. did the statistical analysis and data interpretation. W.Y.L. and J.S.H. assisted the analysis. M.T.S. did the genetic sample preparation and Sanger sequencing. E.S.W.N. provided the expression data. P.K.T., M.Y. and N.D.N. recruit and clinically characterized the patients.
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The study was approved by the institutional review board of The University of Hong Kong together with the Hospital Authority (IRB: UW 06-349T/1374).
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All participant information was anonymized and unique ID codes were presented in this manuscript. Publication of the de-identified results from all consenting participants was approved.
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Tang, C.S., Zhuang, X., Lam, WY. et al. Uncovering the genetic lesions underlying the most severe form of Hirschsprung disease by whole-genome sequencing. Eur J Hum Genet 26, 818–826 (2018). https://doi.org/10.1038/s41431-018-0129-z
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DOI: https://doi.org/10.1038/s41431-018-0129-z
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