About

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 Monica Erazo

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Hirschsprung Overview

What is Hirschsprung disease

Hirschsprung disease (abbreviated as HSCR) is a problem with the way the gut develops and is present from birth. About 1 in 5000 babies is born with HSCR, though this rate varies two-fold across different ethnic groups for reasons still not fully understood.

What causes Hirschsprung disease?

The gut or gastrointestinal tract is lined by nerve cells (100 million of them). Some of these nerve cells sense food in the gut and others work to move food through the gut by causing the wave-like contraction (squeezing) and relaxation (expanding) necessary for passing stool.

HSCR arises when certain nerve cells in the gut (called ganglion cells) fail to develop and mature correctly. This occurs during the first trimester of pregnancy while the embryo is developing in the womb. Ganglion cells arise from a group of cells called neural crest cells, which migrate to the gut and then develop into nerve cells. In Hirschsprung disease, the cells may fail to migrate to the gut, or once in the gut they may fail to survive, multiply, or develop correctly. This results in an ‘aganglionic’ segment (a segment lacking ganglion cells), in which contraction and relaxation is absent, making it difficult for stool to pass through. This leads to chronic constipation and the other symptoms of HSCR.

In HSCR the ganglion cells are missing along varying lengths of the gut from the rectum to the small intestine (See diagram of the gut below). The anus (the farthest end of the gut) is almost always affected when someone has HSCR. About 80% of individuals with Hirschsprung disease have “short-segment” disease, affecting only the rectum, sigmoid colon, and sometimes the descending colon. The other 20% have “long segment” which can include part of the transverse and ascending colons, the total colon, or even extend to parts of the small intestine. (Note: There are different definitions of long segment Hirschsprung disease. Some define it as lack of ganglion cells in the intestine past the sigmoid region, and others say it means beyond the descending colon/splenic flexure.)

Photo courtesy of: Blausen.com staff (2014). “Medical gallery of Blausen Medical 2014”. WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436. – Own work, CC BY 3.0.

What are the symptoms of Hirschsprung disease?

Hirschsprung disease is most often diagnosed within the first week after birth. However, some people are diagnosed later in childhood and as adults, though they have had digestive system problems their whole lives. Symptoms of Hirschsprung disease include constipation, abdominal distension (swelling of the belly), vomiting, decreased appetite, cramping, and failure to gain weight, grow or develop at the expected rate. One of the first signs in a newborn may be not passing meconium (the first bowel movement) within 24-48 hours after birth. Some people with HSCR also develop enterocolitis, an infection of the bowel requiring immediate medical care. Signs of enterocolitis are diarrhea, abdominal distention and fever.

How is Hirschsprung disease diagnosed?

There are several tools used to find out if someone has Hirschsprung disease:

Barium enema x-ray: Barium, a chalky liquid, is put into the colon through the anus and coats the inside of the colon. When an x-ray of the gut is taken, doctors can see the colon. If Hirschsprung disease is present, a funnel-like “transition zone” may be seen. In the part without nerve cells, the colon will appear to be of normal size or somewhat narrowed. In the area above this, the colon may look expanded. The stool that cannot be passed backs up and the colon is stretched and enlarged around it. Seeing the transition zone is a clue that a person may have Hirschsprung disease.

Rectal manometry: The doctor inflates a small balloon inside the rectum. Normally, the anal muscle will relax. If it doesn’t, HSCR may be the problem.

Rectal biopsy: The definitive diagnosis of Hirschsprung disease is made by a rectal biopsy. During the biopsy a small piece of tissue is removed from the rectum. Doctors view the tissue sample under a microscope and look for ganglion cells (nerve cells). If no nerve cells are seen, Hirschsprung disease is diagnosed.

How is Hirschsprung disease treated?

Treatment for Hirschsprung disease consists of surgery to remove the part of the gut without nerve cells and re-connect the remaining intestine to the anus so stool can pass out of the body. This is called a “pull-through” surgery. There are various surgical techniques and methods used. Some patients may need a temporary or permanent ostomy (opening of the intestines to the outside of the body by a hole in the abdomen, through which stool passes), as part of surgical treatment.

The long-term outcome of surgery for Hirschsprung disease is generally good, with most patients having normal or almost normal bowel habits. Some people do have continuing problems with frequency of bowel movements, constipation/diarrhea, leakage of stool from the anus, and recurrent episodes of enterocolitis.

**Because we are a lab of genetic researchers, not medical doctors, we are not experts in the diagnosis and treatment of Hirschsprung disease. Below are two websites that focus more on these aspects of the disease. You should always talk with your doctor about any personal medical concerns.**

National Digestive Diseases Information Clearinghouse

American Pediatric Surgical Association

Disease Genetics

Is Hirschsprung disease genetic?

Yes, there is a variety of evidence to show that Hirschsprung disease is caused by genetic factors.

The ganglion cells, which are missing in all or part of the colon in people with HSCR, come from the neural crest of the embryo. If these neural crest cells do not move into all parts of the colon or fail to grow and mature there, HSCR can result. (see “What causes Hirschsprung disease?) These processes are controlled through complex chemical signals, and genes are responsible for this. Studies done in mice show that removing these genes or their ability to work severely affects how the gut develops.

Hirschsprung disease commonly occurs as part of a syndrome (defined as a combination of birth defects and/or health problems that have the same underlying genetic cause). This also lends support to its genetic basis. Some of these syndromes include problems with other cells that come from the neural crest, such as changes in hair, eye or skin color, and vision or hearing loss.

An individual with HSCR is more likely to have a sibling (brother or sister) or child with HSCR, compared to an individual without HSCR. This is more evidence that there is a genetic component to the disease.

The environment is currently not thought to play a major role in whether or not someone has HSCR. There is no environmental factor proven to be linked to the disease, although some have been suggested. Therefore, as far as we know, there is nothing a mother could have done during pregnancy to cause or prevent HSCR.

Have changes in any genes been found to cause Hirschsprung disease?

By comparing the DNA of people with HSCR and their affected and/or unaffected family members, at least ten different genes have been shown to have a role in causing Hirschsprung disease:

RET GDNF NRTN EDNRB PHOX2B EDN3 ECE1 SOX10 ZFHX1B TCF4

Hirschsprung disease can occur when genetic changes (mutations) happen in one or more of these genes in a person. These genes are thought to be important in the development of the gut. So when they are not working right, it may lead to disease. Researchers are also still searching for other genes involved in HSCR because the above genes don’t explain all the cases of Hirschsprung disease.

Is Hirschsprung disease inherited?

The genetic changes that lead to Hirschsprung disease can be new in the person with HSCR or can be inherited (passed down from a parent). Some people may have a new gene change that is not present in either parent, but arose in the single egg or sperm that made them. Other people with HSCR may have inherited, from their parents, a gene change or combination of genetic changes that gave rise to Hirschsprung disease. The parents may or may not have HSCR. In most cases, a person with HSCR is the first person in their family to have the disease.

What is the inheritance pattern of Hirschsprung disease?

Overall, Hirschsprung disease has an unpredictable pattern of inheritance. Most HSCR cases appear to be multigenic, meaning multiple altered genes are involved in causing the disease. Those with Hirschsprung disease may have inherited genetic changes in one or more genes involved in HSCR from one or both parents. In the parents, these subtle changes usually do not cause disease, but are “susceptibility factors.” If a child inherits a specific combination of these changes or adds a new genetic change, however, Hirschsprung disease can result.

One way to think of the multigenic inheritance of Hirschsprung disease is to compare it to filling a cup. Let’s say Hirschsprung disease results when a certain threshold is crossed – the cup gets full. If each of the parents’ genetic cups is partly full, and they pass on a certain amount to their child, the cup of genes may reach high enough levels that it becomes full, causing Hirschsprung disease. The threshold concept is characteristic of multigenic, or “complex”, inheritance.

In a small fraction of HSCR families, there are affected individuals in several generations. This suggests that there is one genetic change that causes HSCR in the family being passed down through the generations. We call this dominant inheritance. If someone inherits this genetic change they are at high risk for having HSCR. In these families, the chance for an affected person to have a child with Hirschsprung disease is up to 50%. However, because not all individuals who inherit a genetic change predisposing to HSCR will have the disease, even in these families HSCR may appear to skip generations.

If a person has Hirschsprung disease what are the chances that their siblings or children will also have it?

Once a couple has had one child with Hirschsprung disease, the chances of having another are higher than that of the general population. The chance of passing on Hirschsprung disease, or of having another child with it, depends on many factors, including:

whether there are other family members with Hirschsprung disease,
length of the segment involved,
gender of the person affected,
gender of the baby, and
whether there is an associated syndrome in the person with Hirschsprung disease.

In 1990, our laboratory did a study to estimate the chances of a person with HSCR having a sibling (brother or sister) or child with the disease, based on the above factors. The results are shown in the table below. Please keep in mind that the numbers in the table came from looking at a large number of families with each set of factors and calculating an “average” chance. This means that some families, based on their unique genetic makeup, will actually have higher, while others will have lower, chances of having another child with HSCR than the estimate in the table. We also know that a sibling or child of an individual with Hirschsprung disease may have a different length of colon affected than their relative.

*Individuals with HSCR as part of a syndrome or with certain family histories may have a very different chance to have an affected sibling or child than what is in this table. Additionally, the numbers in this table do not apply in families where more than one person has HSCR. Therefore, it is important that anyone interested in their chances of having a child with HSCR discuss how and if these numbers apply to their family with their doctor, and preferably with a geneticist or genetic counselor.*

Table 1. Estimated chance of recurrence (in %) in relatives for the different segment lengths of HSCR. Here is an example of how to read this table: if you have a son with long-segment HSCR, and your next child is a girl, her chance to have HSCR is 7-9%. Your son’s chance to have a son with HSCR is 16-19%. Adapted from Badner et al. Am.J.Hum.Genet. 46: 569-580 (1990).

Predicting chances of recurrence will become more specific and more accurate once researchers identify all the genes involved in HSCR and better understand the disease at the genetic level.

As mentioned above, the best way to get a risk assessment specific to you is to see a geneticist or genetic counselor. You can find one in your area by going to www.nsgc.org, clicking on “Find a Counselor”, and then searching by city or zip code. A genetic counselor would also be able to tell you whether any genetic testing is appropriate for your situation, as it is more likely to provide information for some people than others. The counselor would need to arrange this testing for you.

Why are more boys affected with HSCR than girls?

What about when Hirschsprung disease occurs with other health problems?

Hirschsprung disease is the only health concern in the majority of people who have it. However, about 30% of people with Hirschsprung disease were born with additional health problems. If that is the case, it may be due to chance occurrence, or the person may have a “syndrome.” A syndrome is a combination of birth defects and/or health problems that have the same underlying genetic cause. If a syndrome is suspected, the person with HSCR should be seen by a geneticist (a genetics doctor). The chance of recurrence in future children may be affected by whether or not a syndrome is present.

What are some of these syndromes?

Chromosome abnormalities

About 12% of cases of Hirschsprung disease occur as part of a syndrome caused by a chromosome abnormality. The most common chromosome abnormality that includes Hirschsprung disease is Down syndrome. About 2-10% of individuals with Hirschsprung disease have Down syndrome. (Down syndrome occurs when there is an extra copy of chromosome 21, and it is generally diagnosed at birth. Some of the features common in Down syndrome include characteristic facial features, congenital heart defects, and developmental delays). Hirschsprung disease has also been found in people with certain parts of a chromosome missing, and study of these patients has helped in finding some of the Hirschsprung genes.

Single-gene syndromes

Another 18% of Hirschsprung disease cases occur with other congenital anomalies. In some cases, the combination of anomalies is recognized as a known syndrome caused by changes in a single gene. In other cases, there is no known syndrome or single gene change that can account for the multiple anomalies. Some of the syndromes that include Hirschsprung disease are:

Waardenburg syndrome, type IV (WS4) – People with WS4 have changes in pigment (such as different colored eyes, or a white patch of hair), deafness, and are more likely to have Hirschsprung disease. WS4 can be caused by mutations in the EDNRB, EDN3, or SOX10 genes. It is most often inherited in an autosomal recessive pattern but can also show autosomal dominant inheritance.

An example of different colored eyes in Waardenburg syndrome, type IV. Reproduced from Otolaryngology Houston, www.ghorayeb.com

Congenital Central Hypoventilation syndrome (CCHS) – Individuals with CCHS have problems with their autonomic nervous system that results in normal breathing while awake but hypoventilation when sleeping. A subset of these patients also have Hirschsprung disease and are predisposed to developing neural crest derived tumors such as neuroblastomas. CCHS is generally diagnosed shortly after birth and is caused by mutations in the PHOX2B gene.

Some other single-gene syndromes that can include Hirschsprung disease are: Mowat-Wilson syndrome, cartilage-hair hypoplasia syndrome, Goldberg-Shprintzen syndrome and Smith-Lemli-Opitz syndrome.

Is there another syndrome caused by changes in the RET gene?

Multiple Endocrine Neoplasia Type 2 (MEN2) is an inherited cancer syndrome. People who have MEN2 are at increased risk to get medullary thyroid cancer (MTC), pheochromocytoma (tumor of the adrenal gland), and parathyroid tumors. MEN2 includes 3 slightly different syndromes, including MEN2A, MEN2B, and FMTC (familial medullary thyroid cancer). Like Hirschsprung disease, it is caused by mutations in the RET gene; however, a different type of mutation usually causes MEN2 and the mutations occur in a very specific part of the gene. Individuals have been described who have both Hirschsprung disease and an MEN2-associated RET mutation and cancer. A person with Hirschsprung disease and a personal or family history of endocrine tumors should see a doctor for diagnosis, testing options, and possible monitoring. In 2009, a taskforce of the American Thyroid Association published a recommendation that testing for MEN-associated RET mutations be considered in all patients with Hirschsprung disease because if a mutation that increases cancer risk is found lifesaving preventive and screening options are available. If you wish to learn more about this testing, discuss it with your doctor and ask about a possible referral to a geneticist or genetic counselor.

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.

Is there genetic testing available for Hirschsprung disease?

Yes, but it is only available for one of the genes found to play a role in HSCR. This is the RET gene–the main gene implicated in Hirschsprung disease. It is estimated that a genetic change (mutation) will be found in the RET gene in about 15-35% of isolated cases (individuals with no family history), and about 50% of individuals with a family history of Hirschsprung disease. For long segment and total colonic Hirschsprung disease, a mutation will be found in about 70-80% of cases. In short segment disease, the likelihood of finding a mutation is generally lower, about 10-35%. If it looks like someone may have Hirschsprung disease as part of a syndrome, a doctor may suggest a different genetic test specific to that syndrome instead of RET gene testing.

How can I get the genetic test?

Some people are more likely to get useful results out of RET testing than others and the results can, in some cases, be difficult to interpret. Due to these complexities, you should speak with a genetic counselor or doctor to determine if the test is right for you. This person will also discuss the pros and cons of genetic testing, including the possibility of genetic discrimination. The test must be ordered by your doctor or genetic counselor. The laboratory that does the testing sends your results to the person who ordered the test, who would then discuss the results with you. You may also wish to check with your insurance company before ordering the test to see if it is covered.

What will my results tell me?

Positive (+) – A positive result means that a change is found in the RET gene and the lab knows or believes that the change (a mutation) makes someone more likely to have Hirschsprung disease. The mutation helps explain the occurrence of HSCR in that individual. It will also mean that any children of that individual are at 50% risk to inherit the mutation. However, it is important to remember that children who inherit a RET mutation do not always have Hirschsprung disease. The type of mutation cannot tell us whether or how severely a person will be affected, but research on this is underway.

Negative (-) – If no change is found in the RET gene, no further information has been gained. There could be a mutation in the RET gene that cannot be found with current testing, or there could be a mutation in a totally different gene (or no gene) that is causing Hirschsprung disease. However, there is no other genetic testing available at this time.

Variant of Unknown Significance (VUS) – A change was found in the RET gene, but the lab and your doctor are not sure whether or not it plays a role in Hirschsprung disease. We all have benign variants in our DNA or genetic changes that do not affect our health. A VUS could be a change that makes someone more likely to have HSCR, or it might be one of these benign variants. If there are other family members with HSCR, sometimes testing them can help sort out the meaning of the genetic change, but often there is no more testing to be done at this.

If I will see a genetic counselor before the test, what is a genetic counselor and how can they help?

Genetic counselors are health professionals with specialized graduate degrees and training in the areas of genetics and counseling. Genetic counselors give information and support to families who have members with birth defects or genetic diseases and to families who may be at risk for a variety of inherited conditions.

A genetic counselor can assist a family who has a member with Hirschsprung disease by:

discussing the chances for another baby to have HSC
exploring genetic testing options
interpreting genetic test results
facilitating personal decision-making about getting testing or uses of test results

To find a genetic counselor in your area, go to www.nsgc.org and click on “Find a Counselor”.

Research Study

Overview

Dr. Aravinda Chakravarti’s laboratory has been studying the genetics of Hirschsprung disease (HSCR) for more than twenty years, and it has played an important role in identifying several genes involved in the development of the condition. However, there is more work to be done in clarifying the genetic basis of HSCR. The purpose of our study is: to continue the search for genes involved in Hirschsprung disease; to further characterize the known genes and study the interactions between them; and to identify additional “modifying” genes that influence whether a particular individual develops HSCR. Our study will hopefully lead to a better understanding of the genetics of HSCR and, further down the road, to improved diagnosis, treatment, and genetic counseling.

Current efforts in our laboratory include:

DNA “Chip” Studies
Sequencing Studies
Animal Models

DNA Chip Studies

Our lab was one of the earliest groups to use DNA “chip” technology for disease gene discovery. These chips contain more than one million sites in the human genome sequence. When researchers put a person’s DNA onto a chip, the person’s DNA binds to the chip at all the spots where the person’s DNA matches up with sites on the chip. The chip is then read by a laser scanner to give the results showing the letter in the DNA sequence of that person at each site on the chip. The chips can not only tell us what letters are at each site, but can also tell us when pieces of the genome are deleted or duplicated. The power of this method comes from being able to look at these million plus sites throughout the genome. Depending on the design of these chips, they can be used for a broad search of the genome or for a more in depth look at selected regions.

We use these chips to find DNA variants (differences in the letters at the sites on the chip) that are present both in individuals with and without disease. If enough variants and enough individuals with disease are studied, we may identify a variant in the genome that is found more often in individuals with disease than in those without disease. This helps us to narrow in on the region of the variant as “suspicious”, in that it might contain a Hirschsprung gene. We also use the chips to find areas of the genome that are deleted or duplicated more often in people with Hirschsprung disease. This again helps us to find areas that are suspicious for having a Hirschsprung gene.

The first stage in our chip studies focused on families where only one family member was affected with short-segment HSCR. We analyzed 220 families (affected child and 2 parents), and are currently following up on an interesting result in variants that points to chromosome 7 as possibly containing a gene involved in causing Hirschsprung disease.

In a second stage, we are now looking at the data from the same 220 families for areas with deleted or duplicated regions of the genome. Additionally, we recently completed a project using specially designed DNA chips to look specifically for deletions and duplications in the 67 genes that have been suggested as likely to contribute to Hirschsprung disease. Samples from 18 patients with Hirschsprung disease of varying segment lengths, some with only HSCR and some with HSCR plus additional congenital anomalies, were included in the study. Findings showed small deletions or duplications in nine patients, present in three different genes. These deletions and duplications were found largely in patients who also had mutations in the RET gene and who had HSCR plus additional anomalies. This suggests a role for these deletions and duplications in modifying the effect of other genetic variants (for example, mutations in the RET gene) and in more severe forms where patients have other anomalies.

A DNA Chip showing tiny dots where DNA has bound to the chip.

Sequencing Studies

Another way to study genes involved in Hirschsprung disease is to use DNA sequencing. Sequencing involves reading letter-by-letter through the gene, which is thousands of letters long. There is a common “spelling” of the gene, and a mutation is a change in the spelling that prevents the gene from working correctly.

One project we are completing in the lab is a comprehensive DNA sequencing study of the RET gene in a large number of patients. This is being done in collaboration with the National Institutes of Health. RET is the main gene implicated in Hirschsprung disease, and our studies suggest that all HSCR patients have at least one variant in RET and possible additional variants elsewhere. 680 individuals were included in this project, which includes 237 individuals with Hirschsprung and their family members. We are trying to classify the different sorts of changes in the gene that are detected and to determine whether a given gene change is a harmful mutation or just a benign variant. Understanding these changes will help with interpreting genetic testing of the RET gene for Hirschsprung disease. So far, we have found very high genetic variability overall. The results have shown many never before seen and rare variants, some of which seem to interact with each other to define severe forms of Hirschsprung. Our ongoing analysis is shedding light on such questions as the contribution of RET to HSCR, the parental origin of mutations, and the role of rare and common mutations. This is the most comprehensive study of the RET gene undertaken to date.

We are also looking at results from DNA sequencing of the EDNRB and SOX10 genes in some of the same individuals included in the RET sequencing study. This is again being done in collaboration with the National Institutes of Health. In smaller projects, we are starting to use DNA sequencing to look at certain genes in participants that have features of a particular syndrome, like Waardenburg syndrome type IV or congenital central hypoventilation syndrome.

Finally, advancing sequencing technologies have now brought techniques that allow us to cost effectively and quickly sequence all the genes in an individual. We are working together with the Broad Institute of Massachusetts Institute of Technology and Harvard University on a project to sequence all of the genes for more than 300 individuals with Hirschsprung disease. This will give us a very large data set of genetic variants present in the individuals studied. We will be working with this data set over the next several years in efforts to determine which variants are likely to cause disease and which are likely to be benign. This project brings great opportunity for identifying new genes that may be associated with Hirschsprung disease, disease causing genetic variants in previously suspected genes, and genetic variants in multiple genes that act together to cause disease.

Animal Models

Studies of model organisms, primarily mouse and fish, have been pivotal to our understanding of Hirschsprung disease (HSCR) and the impact of mutations that contribute to risk to develop the disease. We use animal models in a number of ways. First, they allow us to uncover new genes important in the formation of the nervous system of the gut, which may have mutations contributing to HSCR. Second, we use them to study the relevance and severity of mutations found in patients. Third, we use them to look at the potential for co-operation between mutations where more than one mutation has been identified within a patient. Fourth, animal models have allowed us to discover mutations that lie outside of genes, within control switches that direct when, where and how much a gene should be turned on, a particularly significant advance.

We are currently using zebrafish to look at the function of genes on chromosome 7, which are in the region of interest found by our DNA chip studies discussed above. Our ongoing animal work is not only important to a better understanding of HSCR susceptibility but more broadly to disease susceptibility in general as we learn about how genes function in the developing organism.

The zebrafish, a popular model organism.

Why are researchers so interested in Hirschsprung disease?

Hirschsprung disease is a great model of a “complex” genetic disease. Unlike other conditions where there is a clear pattern of inheritance, most cases of Hirschsprung disease are the first in a family. Additionally, in families that do have multiple affected individuals, it can be seen to skip generations.

The characteristics of Hirschsprung disease that make it complex and interesting to researchers are:

Multigenic (multiple genes) – At least 10 different genes have been implicated in Hirschsprung disease in different patients. (Sometimes also called “oligogenic” meaning “a few genes”.)
Reduced penetrance – Inheriting a disease-causing mutation does not guarantee that a person will develop HSCR. It is still unknown what influences whether or not someone with a harmful gene change will have HSCR. However, penetrance is higher in males than in females.
Variable expressivity – Different family members with HSCR may have different lengths of their colon affected by HSCR.
Non-coding mutations – Genes are made up of “coding” and “non-coding” sequence. Coding regions are used to directly make the proteins that build our bodies and allow it to function. Non-coding regions were at one time thought to be “junk” DNA, but are now known to contain a great deal of information, including areas that control when, where, and how the coding regions of DNA are used. The RET gene was found to have a gene change in a non-coding part of the gene which may account for more of the susceptibility to HSCR than those mutations in the coding region. If so, this would be an important finding in the field of genetics.

“Currently HSCR is probably the best example of an oligogenic disease…” Strachan and Read, Human Molecular Genetics, 2nd ed.

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:

complete a medical/family history questionnaire,
provide informed consent (agreement to participate in the study),
provide medical records about the Hirschsprung disease diagnosis or sign a release for us to request these records
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 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.

Monica Erazo, the research study coordinator can be reached at:

Phone: (212)-263-8069

Monica.Erazo@nyulangone.org

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.

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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

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

1996 - 2000

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.

Links

Helpful Links for Resources/Support for Hirschsprung Disease

National Digestive Diseases Information Clearinghouse

American Pediatric Surgical Association

Cincinnati Children’s Colorectal Center

Information and Support Organizations for Hirschsprung disease

Information about Genetics

Fundraising for Hirschsprung disease research

Hirschsprung Gift Fund at NYU School of Medicine

The HD Gift Fund at NYU School of Medicine is a fund maintained by the Chakravarti laboratory. Donations are used to pay for materials and activities for the Hirschsprung Disease Genetics Study. If you would like to make a donation please contact Magan Trottier by phone at 212-263-8069 or email by clicking on this link. Donations are tax deductible to the extent allowed by law.

Hirschsprung’s Disease: Solving the Puzzle

Hirschsprung’s Disease: Solving the Puzzle is a book written by Nicole Murphy, who is a teacher with a master’s degree in science and health education and who has a son with Hirschsprung disease. It has chapters addressing many topics related to Hirschsprung disease including the symptoms, diagnosis, treatment, and what to expect after surgery. The book is for sale on Nicole’s website and she is donating the proceeds to the NYU School of Medicine HD Gift Fund, which supports genetic research on Hirschsprung disease.

For those interested in more detailed scientific information

Medline

Medline is an excellent online resource for medical information. It includes a dictionary, drug list, and encyclopedia.

Gene Tests

GeneTests has excellent summaries on the genetics, diagnosis, management, and inheritance of many genetic conditions.

PubMed

PubMed is the database used by medical researchers.

OMIM

OMIM has clinical synopses of the medical literature on many genetic conditions.

Contact

CONTACT

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

Tel: (212)-263-8069 Fax:(646)-501-4526

Research Coordinator: Monica Erazo

Tel: (212)-263-8069

Administrative Questions: Veronika Worosz
Laboratory Questions: Hanna Berk-Rauch

LOCATION

CAMPUS MAP