Johns Hopkins Medicine


Thank you for visiting Hirschsprung disease study website! This site has been put together by the laboratory of Aravinda Chakravarti, PhD, where we have a large, ongoing genetic study of Hirschsprung disease. The site gives a brief introduction to what Hirschsprung disease is and gives more detailed information on what we know about the genetic basis of Hirschsprung disease. The site also describes the genetic studies taking place in our laboratory and how people with Hirschsprung disease and their family members can get involved in our studies. Also included are links for additional information sources and support groups dealing with Hirschsprung disease (HSCR).

* Please note: we are not able to help with clinical or diagnostic issues that you or your family member may be having, nor are we able to make referrals to doctors. This site is meant to provide information only and any personal health concerns should be discussed with your doctor.

Please send comments or suggestions to this email address.

Hirschsprung Overview

Disease Genetics

Genetic Testing and Counseling

As discussed on our Hirschsprung disease genetics page, there have been several genes found to play a role in causing Hirschsprung Disease (HSCR). The search is ongoing for more genes involved in HSCR, but some people are interested in finding out if they can get genetic testing now. This page discusses the genetic testing available now through a doctor.

Research Study

Getting Involved

If you or your family member has been diagnosed with Hirschsprung disease (HSCR), we would welcome your participation in our research study!  We need participants with all segment lengths of Hirschsprung disease, with or without a family history of the disease, and with or without other health problems.

Research study volunteers will be asked to:

  1. complete a medical/family history questionnaire,
  2. provide informed consent (agreement to participate in the study),
  3. provide medical records about the Hirschsprung disease diagnosis or sign a release for us to request these records
  4. submit blood samples from the individual(s) affected with Hirschsprung disease and, if available, his/her parents.

For minors or others who cannot provide legal consent, a parent or guardian can provide consent (with appropriate agreement of the minor participant) and complete the study paperwork.

Researchers in our laboratory study the genetic material of individuals with Hirschsprung disease and their family members using a variety of methods.  They look for changes in the genetic material that could lead to HSCR.

The research study coordinator, Magan Trottier, would be happy to speak with you to answer any questions you have about HSCR genetics or our research study.  If you decide to participate, the questionnaire, consent forms, medical records release, and blood collection kit will be mailed to you.  Please note that any costs associated with having your blood drawn will be reimbursed (kindly speak with us first).  Research study volunteers are not paid for participating in the study.

The research study coordinator, Magan Trottier, can be reached at:

Phone: (212)-263-8069


Thank you for your interest in our work.

* Please note unencrypted e-mail sent over the Internet is not secure.  This means that information sent by e-mail could be intercepted and may not remain confidential.

Key Papers

2016 - Present
  • Kapoor A, Auer DR, Lee D, Chatterjee S, Chakravarti A: Testing the Ret and Sema3d genetic interaction in mouse enteric nervous system development. Hum Mol Genet 2017 Mar 7. doi: 10.1093/hmg/ddx084. PMID: 28334784.

  • Tang C S-m, Gui H, Kapoor A, Kim JH, Luzón-Toro B, Pelet A, Burzynski G, Lantieri F, So MT, Berrios C, Shin HD, Fernández RM, Le TL, Verheij JB, Matera I, Cherny SS, Nandakumar P, Cheong HS, Antiñolo G, Amiel J, Seo JM, Kim DY, Oh JT, Lyonnet S, Borrego S, Ceccherini I, Hofstra RM, Chakravarti A, Kim HY, Sham PC, Tam PK, Garcia-Barceló MM: Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease. Hum Mol Genet pii: ddw333, 2016. PMID 27702942.

  • Chatterjee S, Kapoor A, Akiyama JA, Auer DR, Lee D, Gabriel S, Berrios C, Pennacchio LA, Chakravarti A: Enhancer variants synergistically drive dysregulation of the RET gene regulatory network in Hirschsprung disease. Cell 167:355-368, 2016. PMID 27693352. PMC5113733.

2011 - 2015
  • Jiang Q, Arnold S, Heanue T, Kilambi KP, Doan B, Kapoor A, Ling AY, Sosa MX, Guy M, Jiang Q, Burzynski G, West K, Bessling S, Griseri P, Amiel J, Fernandez RM, Verheij JB, Hofstra RM, Borrego S, Lyonnet S, Ceccherini I, Gray JJ, Pachnis V, McCallion AS, Chakravarti A: Functional loss of Semaphorin 3C/ Semaphorin 3D and epistatic interaction with RET are critical to Hirschsprung disease liability. Am J Hum Genet 96:581-596, 2015. PMID 25839327. PMC4385176.

  • Kapoor A, Jiang Q, Chatterjee S, Chakraborty P, Sosa MX, Berrios C, Chakravarti A: Population variation in total genetic risk of Hirschsprung disease from common RET, SEMA3 and NRG1 susceptibility polymorphisms. Hum Mol Genet 24:2997-3003, 2015. PMID 25666438. PMC4406299.

  • Gunadi, Kapoor A, Ling AY, Rochadi, Makhmudi A, Herini ES, Sosa MX, Chatterjee S, Chakravarti A: Effects of RET and NRG1 polymorphisms in Indonesian patients with Hirschsprung disease. J Pediatric Surg 49:1614-1618, 2014. PMID 25475805. PMC4258000.

  • Fernández RM, Bleda M, Luzón-Toro B, García-Alonso L, Arnold S, Sribudiani Y, Besmond C, Lantieri F, Doan B, Ceccherini I, Lyonnet S, Hofstra RM, Chakravarti A, Antiñolo G, Dopazo J, Borrego S: Pathways systematically associated to Hirschsprung’s disease. Orphanet J Rare Dis 8:187, 2013. PMID 24289864. PMC3879038.

  • Jannot AS, Pelet A, Henrion-Caude A, Chaoui A, Masse-Morel M, Arnold S, Sanlaville D, Ceccherini I, Borrego S, Hofstra RM, Munnich A, Bondurand N, Chakravarti A, Clerget-Darpoux F, Amiel J, Lyonnet S: Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease. PLoS One May 6;8(5):e62519. doi: 10.1371/journal.pone.0062519, 2013. PMID 23671607. PMC3646051.

  • Jannot A-S, Amiel J, Pelet A, Lantieri F, Fernandez RM, Verheij JB, Garcia-Barcelo M, Arnold S, Ceccherini I, Borrego S, Hofstra RM, Tam PK, Munnich A, Chakravarti A, Clerget-Darpoux F, Lyonnet S: Males and females differential reproductive rate could explain parental asymmetry of mutation origin in Hirschsprung disease. Eur J Hum Genet 20:917-920, 2012. PMID 22395866. PMC3421120.

  • Jiang Q, Ho YY, Hao L, Nichols Berrios C, Chakravarti A: Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease. PLoS One 6(6):e21219, 2011. PMID 21712996. PMC3119685.

2006 - 2010
  • Arnold S, Pelet A, Amiel J, Borrego S, Hofstra R, Tam P, Ceccherini I, Lyonnet S, Sherman S, Chakravarti A: Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome – Hirschsprung disease association. Hum Mutat 30(5):771-775, 2009. PMID 19306335. PMC2779545.

  • Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK, Ceccherini I, Hofstra RM, Fernandez R; Hirschsprung Disease Consortium: Hirschsprung disease: associated syndromes and genetics. J Med Genet 45:1-14, 2008. PMID 17965226.

2001 - 2005
  • Grice E, Rochelle ES, Green ED, Chakravarti A, McCallion AS: Evaluation of the RET regulatory landscape reveals the biological relevance of a HSCR-implicated enhancer. Hum Mol Genet 14:3837-3845, 2005. PMID 16269442.

  • Kashuk CS, Stone EA, Grice EA, Portnoy ME, Green ED, Sidow A, Chakravarti A, McCallion AS: Genotype-Phenotype correlation in Hirschsprung disease illuminated by comparative RET protein sequence analysis. P Natl Acad Sci USA 102:8949-8954, 2005. PMID 15956201. PMC1157046.

  • Emison ES, McCallion AS, Kashuk CS, Bush RT, Grice E, Lin S, Portnoy ME, Cutler DJ, Green ED, Chakravarti A: A common, sex-dependent mutation in a putative RET enhancer underlies Hirschsprung disease risk. Nature 434:857-863, 2005. PMID 15829955.

  • McCallion AS, Sproat-Emison EE, Kashuk CS, Bush RT, Kenton M, Carrasquillo MM, Jones KW, Kennedy GC, Portnoy M, Green E, Chakravarti A: Genomic variation in multigenic traits: Hirschsprung disease. Cold Spring Harb Sym LXVIII 373-381, 2003. PMID 15338639.

  • McCallion AS, Stames E, Conlon RA, Chakravarti A: Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between Ret and Ednrb. P Natl Acad Sci USA 100:1826-1831, 2003. PMID 12574515. PMC149918.

  • Carrasquillo MM, McCallion AS, Puffenberger EG, Kashuk CS, Nouri N, Chakravarti A: Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet 32:237-244, 2002. PMID 12355085.

  • Marshall DG, Meier-Ruge WA, Chakravarti A, Langer JC: Chronic constipation due to Hirschsprung’s disease and desmosis coli in a single family. Pediatr Surg Int 18:110-114, 2002. PMID 11956774.

  • Bolk Gabriel S, Salomon R, Pelet A, Angrist M, Amiel J, Attie-Bitach T, Olson JM, Hofstra R, Buys C, Steffann J, Munnich A, Lyonnet S, Chakravarti A: Splitting a multigenic disease: segregation at three loci explains sibling recurrence risk in Hirschsprung disease. Nat Genet 31:89-93, 2002. PMID 1195374.

  • Weese-Mayer DE, Bolk S, Silvestri JM, Chakravarti A: Idiopathic Congenital Central Hypoventilation Syndrome: Evaluation of Brain-Derived Neurotrophic Factor Genomic DNA Sequence Variation. Am J Med Genet 107:306-310, 2002. PMID 11840487.

1996 - 2000
  • Bolk S, Pelet A, Hofstra R, Angrist M, Salomon R, Croaker D, Buys C, Lyonnet S, Chakravarti A: A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. P Natl Acad Sci USA 97:268-273, 2000. PMID 10618407. PMC26652.

  • Southard-Smith E, Angrist M, Ellison J, Agarwala R, Baxevanis A, Chakravarti A, Pavan W: The Sox10(Dom) mouse: modeling the genetic variation of Waardenburg-Shah (WS4) syndrome. Genome Res 9: 215-225, 1999. PMID 10077527.

  • Angrist M, Bolk S, Bentley K, Nallasamy S, Halushka M, Chakravarti A: Genomic structure of the gene for the SH2 and pleckstrin homology domain-containing protein GRB10  and evaluation of its role in Hirschsprung disease. Oncogene 17:3065-3070, 1998. PMID 9881709.

  • Angrist M, Jing S, Bolk St, Bentley K, Nallasamy S, Halushka M, Fox G, Chakravarti A: Human GFRA1: Cloning, mapping, genomic structure and evaluation as a candidate gene for Hirschsprung disease susceptibility. Genomics 48: 354-362, 1998.  PMID 9545641.

  • Angrist M, Bolk S, Halushka M, Lapchak P, and Chakravarti A: Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet 14: 341-344, 1996. PMID 8896568.

  • Bolk S, Xie J, Angrist M, Silvestri JM, Weese-Mayer DE, Yanagisawa M, Chakravarti A: Endothelin-3 (EDN3) mutation in a patient with Congenital Central Hypoventilation Syndrome. Nat Genet 13:395-396, 1996. PMID 8696331.

  • Hofstra RMW, Osinga J, Tan-Sindhunata G, Wu y, Kamsteeg EJ, Stulp RP, van Ravenswaaji-Arts C, Majoor-Krakauer D, Angrist M, Chakravarti A, Meijers C, Buys CHM: A homozygous mutation in the human endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype. Nat Genet 12:445-447, 1996. PMID 8630503.

  • Bolk S, Angrist M, Schwartz S, Silvestri JM, Weese-Mayer DE, Chakravarti A: Congenital central hypoventilation syndrome: mutation analysis of the receptor tyrosine kinase RET.  Am J Med Genet 63:603-609, 1996. PMID 8826440.

  • Chakravarti A: Endothelin receptor-mediated signaling in Hirschsprung disease. Hum Mol Genet 5:303-307, 1996. PMID 8852653.

Before 1996
  • Angrist A, Bolk S, Thiel B, Puffenberger EG, Hofstra RM, Buys HCM, Chakravarti A: Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet 4:821-830, 1995. PMID 7633441.

  • Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravarti A: A missense mutation of the Endothelin-B Receptor Gene in Multigenic Hirschsprung’s Disease. Cell 79:1257-1266, 1994. PMID 8001158.

  • Puffenberger EG, Kauffman ER, Bolk S, Matise TC, Washington SS, Angrist M, Weissenbach J, Garver KL, Mascari M, Ladda R, Slaugenhaupt SA, Chakravarti A: Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet 3:1217-1225, 1994. PMID 7987295.

  • Angrist M, Kaufmann E, Slaugenhaupt SA, Matise TC, Puffenberger EG, Washington SS, Lipson A, Cass DT, Reyna T, Weeks DE, Sieber W, Chakravarti A: A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10. Nat Genet 4:351-356, 1993. PMID 8401581.

  • Badner JA, Chakravarti A: Waardenburg syndrome and Hirschsprung disease: Evidence for pleiotropic effects of a single dominant gene. Am J Med Genet 35:100-104, 1990.  PMID 2301458.

  • Badner JA, Sieber W, Garver KL, Chakravarti A: A genetic study of Hirschsprung disease. Am J Hum Genet 46:568-580, 1990. PMID 2309705. PMC1683643.



Center for Human Genetics and Genomics
NYU School of Medicine
Science Building, Room 823 R
435 E 30th Street
New York, NY 10016 USA

Tel: (212)-263-8029 Fax:(646)-501-4526

Administrative Coordinator: Jessica Jaffe
Lab Manager: Dallas Auer