A congenital disorder in which part of the bowel never develops the nerve cells that let it relax. RET is the well-established gene, and this page holds a common variant in it alongside two more from a gene, NRG1, that a genome-wide scan found by accident.
In the developing embryo, nerve cells migrate along the length of the bowel and settle into its wall, forming the network that coordinates muscle contraction and lets stool move through. In Hirschsprung disease, that migration stops early, and a section of bowel — usually the lowest part, near the rectum — is left without those nerve cells. Without them the segment cannot relax, and it blocks what should pass through it.
It is congenital and usually presents in the first days of life, most often as a newborn who fails to pass meconium — the first stool — within 48 hours. It affects roughly 1 in 5,000 live births and is more common in boys.
RET is by far the best-studied gene in this disease. Rare, high-penetrance mutations in it are found in a substantial share of familial cases and a smaller share of sporadic ones, and RET is also the gene behind multiple endocrine neoplasia type 2, an unrelated hereditary cancer syndrome. The variant this page holds under RET, rs2742234, is a common variant identified through genome-wide scanning — not one of the rare, high-penetrance mutations found in affected families. It shifts risk across the general population; it is not the test used when a family already has a Hirschsprung diagnosis and a specific mutation to look for.
RET was already known to be the major locus when a 2009 genome-wide association study in 181 Chinese patients and 346 controls went looking for what else contributes. It found NRG1 — neuregulin 1 — at 8p12, with odds ratios between 1.68 and 1.98 for two intronic markers, and a significant statistical interaction with RET itself: carrying a risk genotype at both genes raised the odds far more than either alone.
A 2016 trans-ethnic meta-analysis of 507 cases and 1,191 controls confirmed that both the RET and NRG1 effects hold across European and Asian ancestries — genuinely universal, in a field where that is not automatic. The same study found a third signal, in SEMA3C/SEMA3D, with a large effect (odds ratio 5.2) — but this one turned out to be specific to European ancestry. The page states that difference rather than treating all three loci as equivalent, because they are not.
NRG1 is not new to this site: it also appears on the thyroid cancer page. The two findings are unconnected — different tissue, different mechanism, the same gene doing unrelated work in two places — and it is worth saying so rather than letting a reader assume a link that is not there.
Hirschsprung disease is diagnosed by rectal biopsy, showing the absence of the nerve cells (ganglion cells) that should be present, sometimes alongside a contrast enema and anorectal manometry. Treatment is surgical — removing the affected segment and connecting healthy bowel to the anus — and most children who have surgery go on to normal or near-normal bowel function, though some have ongoing issues that need long-term follow-up.
The sign that gets this looked for. A newborn who does not pass meconium within 48 hours of birth, or an infant with severe, persistent constipation and abdominal swelling, is evaluated for this. It is a paediatric surgical and gastroenterology diagnosis made on biopsy, not a genetic one, and nothing on this page changes that.
Families with a known, rare, high-penetrance RET mutation are a different situation from what this page describes. In that setting, genetic counselling and targeted testing for the family's specific variant are the relevant tools, and they are decided with a clinical geneticist — not read off a common-variant genotype. The three variants here are common ones from population-scale scans, each shifting risk by a fraction, relevant to understanding the disease's biology rather than to diagnosing or counselling an individual family.
NRG1 also appears on the thyroid cancer page, in an unrelated role.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Hirschsprung Disease comes down to these specific, well-studied positions — not a diagnosis.
Databases, guidelines and references
No — that symptom needs a paediatric evaluation, most likely a rectal biopsy, and should not wait on anything here. The variants on this page each shift risk by a fraction across a population and are not diagnostic.
Not directly. A known rare, high-penetrance RET mutation in a family is assessed through clinical genetic testing and counselling for that specific variant. The RET variant on this page is a different, common one from population-scale studies, and it is not the test used in that situation.
Coincidence of the gene, not of the biology. NRG1 does different jobs in different tissues, and its role in the developing bowel nerve network here is unrelated to its role in thyroid tissue on that page.
No. The 2016 study that found it reported the association as specific to European ancestry, distinct from RET and NRG1, whose effects held across European and Asian ancestries in the same study.
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