This grant proposal requests a fourth cycle of funding to explore and expand our understanding of the genetic basis of Hirschsprung disease (HSCR). From the genesis of these studies until today, we have established HSCR as a model complex disorder by: (1) demonstrating that HSCR shows oligogenic inheritance;(2) discovering at least 6 (RET, GDNF, EDNRB, EDN3, SOX10, SEMA3) of the 12 genes known for this disorder;(3) demonstrating genetic interactions between RET and EDNRB signaling (in humans and mouse models) and their downstream transcriptional consequences, as an explanation of the reduced penetrance;(4) discovering the role of common polymorphisms at RET and SEMA3 on HSCR and the molecular basis of this association by in vitro and in vivo analyses;and, (5) assembling and maintaining a database/sample repository (International Hirschsprung Disease Consortium) and a public information resource for ascertaining new cases and families. This grant describes four sets of specific aims that have the goal of identifying a large number of susceptibility genes for HSCR by virtue of them harboring many more dosage and sequence mutations than would be expected by chance. First, we will confirm our recent discovery of SEMA3 as a HSCR locus;second, we will perform focused genetic screens of dosage mutations at all human genes and a genome-wide association study for common susceptibility variants;third, we will target DNA sequencing on a set of 2,000 genes and target loci (~10% of the coding genome) that have emerged from these prior genetic screens.
A fourth aim will be to continue sampling new cases and families, over and above those being collected by members of the International Hirschsprung Disease Consortium, and expand our information resource. We have focused this research on gene discovery and on primary functional analysis leading to specific identification of genes, rather than a deeper understanding of mechanisms of pathogenesis. This choice, a minor departure from our tactic in the last cycle and not possible before, is occasioned by the realization that we have identified very few of the HSCR genes and that many more can now be discovered using new technologies. A better map of this 'HSCR gene universe'will allow a better choice of which mechanisms to investigate in a deeper fashion.

Public Health Relevance

Hirschsprung disease (HSCR) is the most common birth defect due to a functional intestinal obstruction. Molecular genetic studies are ideal for identifying the cellular defects in enteric neuroblasts and their interacting cells intrinsic to this disorder. We propose major innovative molecular studies for identifying the specific genes and how they lead to HSCR.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD028088-18
Application #
8056596
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Henken, Deborah B
Project Start
1991-04-01
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
18
Fiscal Year
2011
Total Cost
$611,181
Indirect Cost
Name
Johns Hopkins University
Department
Genetics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fadista, João; Lund, Marie; Skotte, Line et al. (2018) Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus. Eur J Hum Genet 26:561-569
Gui, Hongsheng; Schriemer, Duco; Cheng, William W et al. (2017) Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes. Genome Biol 18:48
Chatterjee, Sumantra; Kapoor, Ashish; Akiyama, Jennifer A et al. (2016) Enhancer Variants Synergistically Drive Dysfunction of a Gene Regulatory Network In Hirschsprung Disease. Cell 167:355-368.e10
Tang, Clara Sze-Man; Gui, Hongsheng; Kapoor, Ashish et al. (2016) Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease. Hum Mol Genet 25:5265-5275
Kapoor, Ashish; Jiang, Qian; Chatterjee, Sumantra et al. (2015) Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms. Hum Mol Genet 24:2997-3003
Swaminathan, Maya; Oron, Assaf P; Chatterjee, Sumantra et al. (2015) Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections. Pediatr Dev Pathol 18:466-76
Jiang, Qian; Arnold, Stacey; Heanue, Tiffany et al. (2015) Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability. Am J Hum Genet 96:581-96
Gunadi; Kapoor, Ashish; Ling, Albee Yun et al. (2014) Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease. J Pediatr Surg 49:1614-8
Jannot, Anne-Sophie; Pelet, Anna; Henrion-Caude, Alexandra et al. (2013) Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease. PLoS One 8:e62519
Jannot, Anne-Sophie; Amiel, Jeanne; Pelet, Anna et al. (2012) Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease. Eur J Hum Genet 20:917-20

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