Background: Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance. Many susceptibility genes including RET, the major HSCR gene, and several linked regions and associated loci have been shown to contribute to disease pathogenesis. Nonetheless, a proportion of patients still remains unexplained. Copy Number Variations (CNVs) have already been involved in HSCR, and for this reason we performed Comparative Genomic Hybridization (CGH), using a custom array with high density probes.
Results: A total of 20 HSCR candidate regions/genes was tested in 55 sporadic patients and four patients with already known chromosomal aberrations. Among 83 calls, 12 variants were experimentally validated, three of which involving the HSCR crucial genes SEMA3A/3D, NRG1, and PHOX2B. Conversely RET involvement in HSCR does not seem to rely on the presence of CNVs while, interestingly, several gains and losses did co-occur with another RET defect, thus confirming that more than one predisposing event is necessary for HSCR to develop. New loci were also shown to be involved, such as ALDH1A2, already found to play a major role in the enteric nervous system. Finally, all the inherited CNVs were of maternal origin.
Conclusions: Our results confirm a wide genetic heterogeneity in HSCR occurrence and support a role of candidate genes in expression regulation and cell signaling, thus contributing to depict further the molecular complexity of the genomic regions involved in the Enteric Nervous System development. The observed maternal transmission bias for HSCR associated CNVs supports the hypothesis that in females these variants might be more tolerated, requiring additional alterations to develop HSCR disease.
Keywords: Candidate genes and regions; Comparative genomic hybridization; Copy number variations; Custom array; Hirschsprung disease.
Conflict of interest statement
The authors declare that they have no competing interests.
Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease.PLoS One. 2011;6(6):e21219. doi: 10.1371/journal.pone.0021219. Epub 2011 Jun 21. PLoS One. 2011. PMID: 21712996 Free PMC article.
Novel MLPA procedure using self-designed probes allows comprehensive analysis for CNVs of the genes involved in Hirschsprung disease.BMC Med Genet. 2010 May 11;11:71. doi: 10.1186/1471-2350-11-71. BMC Med Genet. 2010. PMID: 20459765 Free PMC article.
Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease.Gastroenterology. 2018 Jul;155(1):118-129.e6. doi: 10.1053/j.gastro.2018.03.034. Epub 2018 Mar 28. Gastroenterology. 2018. PMID: 29601828
[From monogenic to polygenic: model of Hirschsprung disease].Pathol Biol (Paris). 1998 Nov;46(9):705-7. Pathol Biol (Paris). 1998. PMID: 9885824 Review. French.
The developmental etiology and pathogenesis of Hirschsprung disease.Transl Res. 2013 Jul;162(1):1-15. doi: 10.1016/j.trsl.2013.03.001. Epub 2013 Mar 22. Transl Res. 2013. PMID: 23528997 Free PMC article. Review.
Cited by 1 article
Genetic variants in RET, ARHGEF3 and CTNNAL1, and relevant interaction networks, contribute to the risk of Hirschsprung disease.Aging (Albany NY). 2020 Mar 6;12(5):4379-4393. doi: 10.18632/aging.102891. Epub 2020 Mar 6. Aging (Albany NY). 2020. PMID: 32139661 Free PMC article.