Hirschsprungs Disease

Rare Gut Condition a Model for Study of Genetic Diseases

Hirschsprungs Disease | Johns Hopkins Medicine

Hirschsprung disease (HSCR)—a rare condition where the failure of gut nerves to develop before birth leads to impaired bowel contractions that prevent infants from passing stool—is more predictable from an individual’s genetic makeup than previously envisioned. This is the finding of a study published online April 11 in the New England Journal of Medicine.

The study of this condition, which has the hallmarks of a complex disorder caused by a combination of genetic, environmental, and other factors, also provides insights into yet more complex diseases schizophrenia and autism, say the study authors.

“We are finally understanding the genetics of HSCR well enough to clarify the multiple key genes involved, the cellular mechanisms they alter, and the molecular targets against which drugs could be targeted to provide personalized treatment to patients,” says senior study author Aravinda Chakravarti, PhD, director of the Center for Human Genetics and Genomics at NYU Langone.

“This condition results from three different classes of genetic changes, including previously underappreciated regions that regulate genes,” adds Dr. Chakravarti, who did much of the work for the current study while at Johns Hopkins University. He joined NYU Langone in April 2018.

HSCR is rare, occurring in about one of every 5,000 live births, and is inherited in more than 80 percent of cases—a “striking” genetic proportion, say the authors.

Its medical impact is high as missing nerves in the bowel prevent infants from passing stool, cause blockages, and require surgery to remove all affected parts of the bowel.

Even after surgery, up to 50 percent of patients experience continual bowel problems and can face lifelong, life-threatening, intestinal infections.

Deeper into the Human Genome

The current study is unique, say the authors, in that it examined all classes of genetic changes in the complete set of human genetic material (our genome), whether currently associated with HSCR or not, in 190 patients.

These included patients with familial (multiple family members affected), sporadic (one person affected in a family), or syndromic (HSCR associated with other features) forms of the disease.

By doing so, the research team arrived at the first comprehensive list of genetic variants that confer different degrees of risk across different groups of HSCR patients.

The study reflects advances in the understanding of the human genome; for decades, scientists thought of disease risk only in terms of changes in genes, or the sequences of DNA letters that encode instructions for making proteins, functional units in cells that have a wide array of roles. Subsequently, scientists learned that the genome also contains a vast, regulatory DNA code that specifies when genes are turned on and off and when and how much of a protein to make.

This new study shows that in HSCR, at least half of the risk is conferred by abnormal versions of this regulatory DNA code that control four distinct HSCR genes.

On top of this, the team linked increased risk for the disease to very rare changes in the structures of 24 specific genes, seven of which were newly identified here. Even more dramatic increases of risk were conferred by the even rarer occurrence of extra or missing pieces of chromosomes, structures into which DNA and genes are tightly packaged in order to fit into a cell.

Surprisingly, regulatory DNA errors were responsible for the majority of HSCR risk across all patients because they were so much more common than rare structural changes in genes, or even rarer chromosome changes, despite the greater individual potency of the latter two classes of changes. The study authors concluded that the total risk of HSCR varies 67-fold in those with any genetic risk factor, increasing with each disease-causing variant present.

Past studies had shown that HSCR arises from genetic abnormalities in genes that control how a set of early cells (neural crest progenitor cells) in the embryo mature into nerve cells that line the gut. Past work had also focused on code changes in the RET gene, a gene that normally relays chemical signals to tell gut neural crest progenitor cells to multiply and form a fully functioning gut.

The current study showed that 48.

4 percent of HSCR patients have changes in either the RET gene or a gene within a large network that controls RET and influences how nerve cells grow, mature, and form connections to pass on developmentally important signals. this and past work, the team proposes that understanding such networks, not simply individual genes, is crucial to understanding human disease.

“Our findings argue that patients should be tested for genetic variations across their complete set of DNA, and not just in important genes RET, to catch both more frequent and rare contributors as we tailor counseling and treatment to individuals,” says Dr. Chakravarti.

Along with Dr.

Chakravarti, study authors included first author Joseph Tilghman, Albee Ling, Tychele Turner, Maria Sosa, Sumantra Chatterjee, Ashish Kapoor, Khanh-Dung Nguyen, and Courtney Berrios from the Center for Complex Disease Genomics at Johns Hopkins University School of Medicine. Additional study authors were Niklas Krumm, Bradley Coe, and Evan Eichler of the Department of Genome Sciences at University of Washington, as well as Namrata Gupta and Stacey Gabriel of the Broad Institute of MIT and Harvard.

The studies reported here were supported in part by National Institutes of Health grants R37 HD28088, R01 MH101221, and U54 HG003067.

Learn more about how to support Dr. Chakravarti’s Hirschsprung disease study.

Media Inquiries

Greg WilliamsPhone: 212-404-3533


Source: https://nyulangone.org/news/rare-gut-condition-model-study-genetic-diseases


Hirschsprungs Disease | Johns Hopkins Medicine

Hirschsprung Disease Genetics Study

Dr. Aravinda Chakravarti’s laboratory at New York University has been investigating the genetics of Hirschsprung disease (HSCR) for more than fifteen years.

The purpose of our study is to continue the search for genes involved in Hirschsprung disease and to further characterize the known genes and the interactions between them.

  Our study will hopefully lead to a better understanding of the genetics of HSCR and, further down the road, improved diagnosis, treatment, and genetic counseling.

We ask study volunteers to:

  • complete a medical/family history questionnaire
  • provide access to some medical records
  • submit blood (or cheek swab/saliva) samples from the individual(s) affected with Hirschsprung disease and his/her parents (if available)

If you are interested, a kit containing all the materials necessary to participate can be sent to you.  There will be no cost to you.

For more information please contact the study coordinator, Monica Erazo, at 212-263-8069 or hirschsprung@nyulangone.org.

You can also visit our study website at: https://aravindachakravartilab.org/hirschsprung-study/#getinvolved

Neural Tube Defect Research

Center for Human Genetics
Duke University Health System

There are two types of NTDs. The most common type are called the open NTDs. Open NTDs occur when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae (back bones).

Examples of open NTDs are spina bifida (myelomeningocele), anencephaly, and encephalocele. Rarer types of NTDs are called closed NTDs. Closed NTDs occur when the spinal defect is covered by skin.

Common examples of closed NTDs are lipomyelomeningocele, lipomeningocele, and tethered cord.

Neural Tube Defects Research Review

NTDs are one of the most common birth defects, though their causes are not well understood. The formation of the neural tube during development is a complex process, and the goal of our project is to discover the genetic and environmental factors that contribute to NTDs. One major step in research is to gather data on a large number of families.

Currently, the Center for Human Genetics (CHG) has enrolled more than 1200 families. We will need to enroll another 500-1000 families before some of the laboratory studies can be completed.

We continue to collaborate with Myelodysplasia clinics around the country, presenting information at local and national Spina Bifida Association of America conferences, and speaking with families interested in the study.

In the laboratory, our goal is to find genes that cause or contribute to NTDs. There are two major strategies scientists are using:

  • genome scan – systematically searching each chromosome, looking for areas which may harbor genes that cause or contribute to NTDs
  • candidate gene analysis – studying genes of known function that could potentially be involved in neural tube development. Examples of candidate genes include the many genes involved in the folic acid metabolism pathway, genes known to cause NTDs in animals, and genes involved in chromosomal rearrangements in individuals who also have NTDs.

Neural Tube Defect Study Team

A project of this magnitude requires the efforts of many. These experienced CHG researchers-with the help of interested families-continue to search for genes that cause NTDs.

If your family is interested in learning more about this NTD research or in participating, please contact us toll free at (866) DUKE-NTD (866) 385-3683 or e-mail ntd@chg.duhs.duke.edu.

Research – IVF and the Development of Cloacal-Bladder Exstrophy-Epispadias Complex

Invitation to participate in a research study regarding IVF and Bladder Exstrophy
Johns Hopkins Medical Institution

Brady Urological Institute

We are researchers in the division of pediatric urology at the Brady Urological Institute of the Johns Hopkins Medical Institution. This center specializes in the care of children born with cloacal exstrohpy, bladder exstrophy, and epispadias.

We also conduct laboratory and clinical research investigating the causative factors and medical needs of children with this complex of congenital defects.

As part of our ongoing efforts to better understand cloacal and bladder exstrophy and epispadias, we are evaluating a potential association between the use of in vitro fertilization (IVF) technologies and the development of the cloacal-bladder exstrophy-epispadias complex.

We would to invite families of children born with cloacal exstrophy, bladder exstrophy, or epispadias who underwent IVF to participate in our study. Participation will require a telephone-administered interview of approximately 15 minutes in length. Interview questions will pertain to parental and child perinatal health.

At the conclusion of the interview, the parent would have the opportunity to provide further detail about his/her child and ask questions of the interviewer. Interviews will be conducted by Dr. Gearhart, chair of the division of pediatric urology at Johns Hopkins, or one of his associates.

The results of the study will be published, but the identity of all participants will remain anonymous.

If you would to participate, please contact the Dr. Gearhart’s office by telephone, e-mail, fax, or postal mail at the information provided below.

Your participation will advance our understanding of the potential causative factors of this complex of defects and may lead to prevention of such defects in future generations.

Thank you for taking the time to consider participating in this study.

John Gearhart, M.D.The James Buchanan Brady Urological InstituteThe Johns Hopkins Medical Institutions600 N. Wolfe StreetBaltimore, MD 21287-2101Telephone: (410) 955-5358Fax: (410) 955-0833

E-mail: jgearhart@jhmi.edu

Source: https://www.pullthrunetwork.org/research/

Hirschsprung Study

Hirschsprungs Disease | Johns Hopkins Medicine

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Source: https://aravindachakravartilab.org/hirschsprung-study/

Hirschsprungs Disease

Hirschsprungs Disease | Johns Hopkins Medicine

Linkedin Pinterest Genetic Disorders

Hirschsprung's disease (also called colonic aganglionosis) is a blockage of the large intestine due to improper muscle movement in the bowel. It is a congenital condition, which means it is present from birth.


In Hirschsprung's disease, certain types of nerve cells (called ganglion cells) are missing from a part of the bowel. In areas without such nerves, the muscle within the bowel wall does not contract to push material through, which causes a blockage. Intestinal contents build up behind the blockage, swelling the bowel and abdomen.

Hirschsprung's disease causes about 25 percent of all newborn intestinal blockages, but is also identified in older babies and children. It occurs five times more often in males than in females. Hirschsprung's disease is sometimes associated with other inherited or congenital conditions, such as Down syndrome.



  • Difficulty or straining with bowel movements
  • Failure to pass meconium (stool) shortly after birth (within 24 to 48 hours)
  • Infrequent but explosive stools
  • Jaundice
  • Poor feeding
  • Poor weight gain
  • Vomiting
  • Watery diarrhea (in the newborn) 

Older children:

  • Constipation that gradually gets worse (patients may need to take laxatives regularly)
  • Fecal impaction
  • Malnutrition
  • Slow growth


Milder cases may not be diagnosed until a later age. During a physical examination, the doctor may be able to feel loops of bowel in the swollen belly. A rectal examination may reveal a loss of muscle tone in the rectal muscles.

Tests used to help diagnose Hirschsprung's disease may include:

  • Abdominal X-ray
  • Barium enema: an X-ray that shows the shape of the rectum and colon
  • Anal manometry: measurement of pressure within the rectum using an inflatable balloon
  • Rectal biopsy: A suction tube is used to collect tissue from the inside of the rectum. This tissue can then be examined under a microscope to determine if ganglion cells are present. Although biopsy results can sometimes be inconclusive, this is usually the best test to determine if a child with symptoms has the disease.


Before the operation, a procedure called serial rectal irrigation helps relieve pressure in (decompress) the bowel. The abnormal sections of colon and rectum must be removed with surgery to permit the child to pass stools easily. The healthy part of the colon is then moved into the child’s pelvis and attached to the anus.

Sometimes this can be done in one operation, but it is often done in two parts (also called a “staged procedure”). If performed in one operation, the surgeon will connect the colon to the anus immediately after removing the abnormal colon and rectum. If performed as a staged procedure, first step is to remove the diseased colon and rectum, followed by a colostomy.

When a colostomy is performed, the cut edge of the large intestine is brought to an opening that is made through the wall of the abdomen. This allows bowel contents to empty into a bag.

Later, when the child’s weight, age and condition have improved, a pull-through procedure is performed, which removes the colostomy and connects the large intestine to the anus to permit the child to pass normal bowel movements.


Symptoms improve or go away in most children after surgery. A small number of children may have constipation or problems controlling stools (fecal incontinence). In general, children who are treated early and those with limited disease (which allows the surgeon to leave more healthy bowel in place) have better outcomes.

Source: https://www.hopkinsmedicine.org/health/conditions-and-diseases/hirschsprungs-disease

NORD (National Organization for Rare Disorders)

Hirschsprungs Disease | Johns Hopkins Medicine

Peña A, Hong AR. Hirschsprung Disease. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:345.

McLaughlin D, Puri P. Familial Hirschsprung’s disease: a systemic review. Pediatr Surg Int. 2015;31:695-700. https://www.ncbi.nlm.nih.gov/pubmed/26179259

Burkardt DD, Graham JM Jr., Short SS, Frykman PK. Advances in Hirschsprung disease genetics and treatment strategies: an update for the primary care physician. Clin Pediatr (Phila). 2014;53:71-81. https://www.ncbi.nlm.nih.gov/pubmed/24002048

Frykman PK, Short SS. Hirschsprung-associated enterocolitis: prevention and therapy. Semin Pediatr Surg. 2012;21:328-335. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462485/

Ralls MW, Coran AG, Teitelbaum DH. Reoperative surgery for Hirschsprung disease. Semin Pediatr Surg. 2012;21:354-363. https://www.ncbi.nlm.nih.gov/pubmed/22985841

Demehri FR, Halaweish IF, Coran AG, Teitelbaum DH. Hirschsprung-associated enterocolitis: pathogenesis, treatment and prevention. Pediatr Surg Int. 2013;29:873-881. https://www.ncbi.nlm.nih.gov/pubmed/23913261

Teitelbaum DH, Coran AG. Primary pull-through for Hirschsprung’s disease. Semin Neonatol. 2003;8:233-41. https://www.ncbi.nlm.nih.gov/pubmed/15001142

Stewart DR, von Allmen D. The genetics of Hirschsprung disease. Gastroenterol Clin North Am. 2003;32:819-837. https://www.ncbi.nlm.nih.gov/pubmed/14562576

Elhalaby EA, Hashish A, Elbarbary MM, et al. Transanal one-stage endorectal pull-through for hirschsprung’s disease: a multicenter study. J Pediatr Surg. 2004;39:345-51. https://www.ncbi.nlm.nih.gov/pubmed/15017550

Puri P, Shinkai T. Pathogenesis of Hirschsprung’s disease and its variants: recent progress. Semin Pediatr Surg. 2004;13:18-24. https://www.ncbi.nlm.nih.gov/pubmed/14765367

Tomita R, Ikeda T, Fujisaki S, et al. Upper gut motility of Hirschsprung’s disease and its allied disorders in adults. Hepatogastroenterology. 2003;50:1959-62. https://www.ncbi.nlm.nih.gov/pubmed/14696442

Griseri P, Pesce B, Patrone G, et al. A rare haplotype of the RET proto-oncogene is a risk-modifying allele in hirschsprung disease. Am J Hum Genet. 2002;71:969-74. https://www.ncbi.nlm.nih.gov/pubmed/12214285

National Institute of Diabetes and Digestive and Kidney Diseases. Hirschsprung Disease. September 2015. Available at: https://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/hirschsprung-disease/Pages/ez.aspx Accessed September 22, 2016.

Parisi MA. Hirschsprung Disease Overview. 2002 Jul 12 [Updated 2015 Oct 1]. In: Pagon RA, Bird TD, Dolan CR, et al., GeneReviews. Internet. Seattle, WA: University of Washington, Seattle; 1993-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1439/ Accessed September 22, 2016.

Kenny S. Hirschsprung Disease. Orphanet Encyclopedia, September 2012. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=388 Accessed September 20, 2016.

University of California San Francisco Pediatric Surgery. Hirschsprung’s Disease. Available at: http://pedsurg.ucsf.edu/conditions–procedures/hirschsprungs-disease.aspx Accessed September 22, 2016.

Cincinnati Children’s Hospital Medical Center. Hirschsprung Disease. June 2015. Available at: https://www.cincinnatichildrens.org/health/h/hirschsprung Accessed September 22, 2016.

Wesson DE. Congenital aganglionic megacolon (Hirschsprung disease. UpToDate, Inc. 2015 Jul 28. Available at: http://www.uptodate.com/contents/congenital-aganglionic-megacolon-hirschsprung-disease Accessed September 22, 2016.

Source: https://rarediseases.org/rare-diseases/hirschsprungs-disease/

Andrew S. McCallion, PhD

Hirschsprungs Disease | Johns Hopkins Medicine


The Queen's Univeristy of Belfast, Northern Ireland
University of Glasgow, Scotland


Dr. Andrew McCallion is an associate professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine. His research focuses on applying functional genetics to human development and disease. Dr.

McCallion was part of a research team at Johns Hopkins whose work explained the interactions between multiple genes resulting in Hirschsprung disease, common disorder with complex genetic inheritance patterns.

This work serves as a model for the dissection of common complex disease.

His research focuses on making the connection between gene sequence (and variation therein) and phenotype through the integrated use of contemporary genomic strategies and model systems (mouse, zebrafish and cell culture).

Dr. McCallion received his B.Sc. in genetics from The Queen's University of Belfast. He earned his Ph.D. in genetics from the University of Glasgow. He completed postdoctoral training at Case Western Reserve University Medical School.

Prior to joining Johns Hopkins, Dr. McCallion was a project leader and staff scientist at Neuropa Ltd. (UK), a biotech startup focused on drug target development for neurodegenerative disorders.

He is a member of the International Mammalian Genome Society, American Society of Human Genetics (ASHG) and Federation of American Societies for Experimental Biology. He was a former Chair of the ASHG program committee, He serves on the editorial board of Genome Research, and is a Faculty of 1000 faculty member in genomics and genetics.

Current Research

My group studies how transcriptional regulatory control is encrypted in genomic sequence, and how variation in regulatory sequences may contribute to phenotype variation and disease risk/presentation. In this work my group employs cutting edge genomic and functional genetic approaches in mice, zebrafish and in vitro, integrating them with computational biology.

Regulatory sequences underlie the cellular diversity that arises during human development, and how cells respond to environmental and genetic insult. Regulatory mutations underlie an array of human diseases. They play a significant role in disease susceptibility and they form the basis of cellular response to insult, aging and stress.

My early work began with studies of neuronal and neural crest development. Efforts in my lab are currently directed at developing cell-type dependent regulatory sequence catalogs and applying them in human population-based studies to predict, identify and validate ly functional variation that associates with disease.

In some of our recent work we have generated large catalogs of putative enhancers in various cell types using ChIP-seq and ATAC-seq (melanoctytes, dopaminergic neurons [ventral midbrain, forebrain, olfactory bulb]).

Further begun to explore how these data can be used to learn the vocabularies of cell-dependent control inform our understanding of functional non-coding variation and the molecular mechanisms of transcriptional control.

  Our emerging work has begun to integrate these analyses with studies of transcriptional heterogeneity within cell-types, using single cell RNA-seq to explore specific neuronal populations and define their Gene Regulatory Networks (GRNs). Our efforts are now focused on the development, validation and integration of regulatory sequence catalog information with the development of GRNs in cell populations and tissues of neurobehavioral disease-relevance.


Gene regulation is the framework on which vertebrate cellular diversity is built. The substantial cellular diversity that characterizes complex integrated cell populations, such as the human central nervous system, must therefore require immense regulatory complexity.

Similarly, the cells comprising the embryonic neural crest, a population that contributes craniofacial cartilage and bone, pigment cells of the skin and hair, neuroendocrine cells and the entire peripheral nervous system to the vertebrate embryo, must face similar challenges in choosing the correct fate.

These cells go awry in a wide array of human disorders Parkinson's disease, Hirschsprung disease, psychiatric disorders and melanoma, and comprise the focus of our efforts.

Although regulatory control acts at many levels, we focus on the roles played by cis-regulatory elements (REs) in controlling the timing, location and levels of gene activation (transcription). However, the biological relevance of non-coding sequences cannot be inferred by examination of sequence alone.

Perhaps the most commonly used indicator of non-coding REs is evolutionary sequence conservation. Although conservation can uncover functionally constrained sequences, it cannot predict biological function, and regulatory function is not always confined to conserved sequences.

At its simplest level, regulatory instructions are inscribed in transcription factor binding sites (TS) within REs. Yet, while many TS have been identified, TS combinations predictive of specific regulatory control have not yet emerged for vertebrates.

We posit that motif combinations accounting for tissue-specific regulatory control can be identified in REs of genes expressed in those cell types. Our immediate goal is to begin to identify TS combinations that can predict REs with cell-specific biological control—a first step in developing true regulatory lexicons.

As a functional genetics laboratory, we develop and implement assays to rapidly determine the biological relevance of sequence elements within the human genome and the pathological relevance of variation therein.

In recent years, we have developed a highly efficient reporter transgene system in zebrafish that can accurately evaluate the regulatory control of mammalian sequences, enabling characterization of reporter expression during development at a fraction of the cost of similar analyses in mice. We employ a range of strategies in model systems (zebrafish and mice), as well as analyses in the human population, to illuminate the genetic basis of disease processes. Our long-term objective is to use these approaches in contributing to improved diagnostic, prognostic and ultimately therapeutic strategies in patient care.

If you are interested in learning more about the work we do or would to inquire about positions available within the lab, please contact Dr. McCallion andy@jhmi.edu.

Selected Publications

1.     Fisher S, Grice EA, Vinton RM, Bessling SL, McCallion AS. (2006) Conservation of RET Regulatory Function from Human to Zebrafish Without Sequence Similarity. Science. 312, 276-279.

2.     Lee D, Gorkin DU, Baker M, Strober BJ, Asoni AL, McCallion, A.S.† and Michael A. Beer† A method to predict the impact of regulatory variants from DNA sequence. Nature Genetics. 2015 Aug;47(8):955-61. †, Co-corresponding authors

3.     Hook PW, McClymont SA, Cannon GH, Law WD, Morton AJ, Goff LA†, McCallion AS†.

Single-cell RNA-seq of dopaminergic neurons informs candidate gene selection for sporadic Parkinson's disease. American Journal of Human Genetics 2018 Mar 1;102(3):427-446. doi: 10.1016/j.ajhg.2018.02.

001 (Cotterman Award winner – Outstanding AJHG paper of 2018) (†, co-corresponding authors)


     McClymont SA, Hook PW, Soto AI, Reed X, Law WD, Kerans SJ, Waite EL, Briceno NJ, Thole JF, Heckman MG, Diehl NN, Wszolek ZK, Moore CD, Zhu H, Akiyama JA, Dickel DE, Visel A, Pennacchio LA, Ross OA, Beer MA, McCallion AS. Parkinson-Associated SNCA Enhancer Variants Revealed by Open Chromatin in Mouse Dopamine Neurons. Am J Hum Genet. 2018 Dec 6;103(6):874-892. doi: 10.1016/j.ajhg.2018.10.018. Epub 2018 Nov 29.

5.     Gould R, Woods C, MIBAVA Leducq consortium, McCallion AS*, Dietz HC* Mutations in ROBO4 explain a fraction of human aortopathy and result in regurgitation and abnormal flow in both zebrafish and mouse mutant models. *, co-corresponding authors. Nature Genetics. 2019 Jan;51(1):42-50. doi: 10.1038/s41588-018-0265-y. Epub 2018 Nov 19. PMID: 30455415

View complete list of publications on PubMed.

Source: https://mcp.bs.jhmi.edu/people/andrew-s-mccallion-phd