Abstract
BackgroundHirschsprung 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.ResultsA 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.ConclusionsOur 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.
Highlights
Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance
Four additional HSCR patients were included as positive controls: two with a de novo deletion at the centromeric region of chromosome 10 [12, 13], one with an inverted duplication at chromosome 22, and another one with a trisomy 21
Besides the major RET gene, other candidate genes and loci were selected for the analysis based on i) linkage with HSCR, ii) association with the disease, iii) mutation in syndromic and isolated HSCR patients, iv) involvement in the transcriptional regulation of RET, and v) preliminary evidence, not confirmed later
Summary
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. HSCR is characterized by increased sibling recurrence risk varying by gender, length of aganglionosis and familial occurrence (up to 80% of cases are sporadic). These observations, together with a distorted sex ratio (M: F = 4:1), make HSCR a model for complex genetic disease. A proportion of HSCR patients still remains unexplained as only 50% of familial and 7– 35% of sporadic HSCR cases can be explained by RET coding variants [1]. The RET gene was discovered following observation of de novo interstitial deletions of 10q11.2 [12, 13] and about 12% of HSCR patients have structural abnormalities [1]
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