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Hirschsprung Disease 2 (HSCR2) via the EDNRB Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
EDNRB 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11005EDNRB81479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Greg Fischer, PhD

Clinical Features and Genetics

Clinical Features

Hirschsprung Disease (HSCR) is characterized by congenital absence of neuronal ganglion cells from a portion of the intestinal tract. Patients are diagnosed with the short-segment form (S-HSCR, approximately 80% of cases) when the aganglionic segment does not extend beyond the upper sigmoid, and with the long-segment form (L-HSCR, about 15%-20% of cases) when aganglionosis extends proximal to the sigmoid (Amiel et al. 2008). In about 5% of cases, aganglionosis affects the entire large intestine (total colonic aganglionosis). Cases with total intestinal HSCR also occur. Affected infants frequently present in the first two months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life, constipation, emesis, abdominal pain or distention, and occasionally diarrhea. However, because the initial diagnosis of HSCR may be delayed until late childhood or adulthood, HSCR should be considered in anyone with lifelong severe constipation. HSCR can also be associated with cardiac defects and autonomic dysfunction. Individuals with HSCR are at risk for enterocolitis and/or potentially lethal intestinal perforation (Parisi 2011).

Hirschsprung Disease as a feature of other disorders [Syndromic HSCR]: While HSCR is observed in 10-15% of Down syndrome patients and some cases of MEN2 (Parisi 2011), it occurs as a constant feature of the following syndromes; Waardenburg-Shah Syndrome [OMIM # 277580], Mowat-Wilson Syndrome [OMIM # 235830], Goldberg-Shprintzen Megacolon Syndrome [OMIM # 609460] and Haddad Syndrome [OMIM # 209880].


Hirschsprung Disease demonstrates a multifactorial or polygenic mode of inheritance with an incidence of 1 in 5000 newborns. There is a male predominance of 3:1 to 5:1 in Hirschsprung disease (Lipson et al. 1990). Incidence of short-segment disease (80% of HSCR) is four times greater in males than in females; while equal numbers of males and females present with long-segment disease (Badner et al. 1990). For L-HSCR cases, the mode of inheritance is compatible with a dominant gene with incomplete penetrance, while for S-HSCR cases, the inheritance pattern is equally likely to be either multifactorial or due to a recessive gene with very low penetrance.

Non-syndromic HSCR has been associated with mutations in at least six genes; RET, EDN3, EDNRB, GDNF, ECE1 and NRTN with mutations in RET accounting for ~50% of cases (Parisi and Kapur 2000). HSCR2 is caused by missense and truncating mutations in EDNRB, which can be inherited as autosomal dominant or recessive. The protein encoded is the endothelin receptor type B, a cell surface protein which functions by interacting with endothelin 3. Together they play a very important role in neural crest cells. Disruption or loss of the EDNRB protein results in the loss of enteric nerve cells that are critical to intestinal development, resulting in Hirschsprung disease.

Mutations in EDNRB are also associated with syndromic HSCR - Waardenburg-Shah syndrome.

Clinical Sensitivity - Sequencing with CNV PGxome

Mutations in EDNRB are associated with non-syndromic HSCR. The clinical sensitivity of our sequencing assay for this gene is currently unknown. However, since mainly small indels, duplications, missense and truncating mutations have been described for this gene associated with Hirschsprung Disease, we believe that our sequencing assay will be able to identify a significant majority of the mutations.

Testing Strategy

This test provides full coverage of all coding exons of the EDNRB gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Histopathological demonstration of absence of enteric ganglion cells in the distal rectum. Absence of ganglion cells in the submucosa of 50-75 sections examined from a biopsy establishes the diagnosis of HSCR and can be confirmed by genetic testing. If monogenic nonsyndromic HSCR is likely, molecular genetic testing of RET should be considered. If a RET mutation is not identified, molecular genetic testing of EDNRB, GDNF, EDN3, ECE1 and NRTN may be considered. If syndromic HSCR is suspected, genetic testing should be considered accordingly.

Individuals with the following symptoms may also consider genetic testing for HSCR (Kessmann 2006):

Infants with bilious vomiting, enterocolitis-associated diarrhea, failure to pass meconium in the first 24 hours of life, infrequent, explosive bowel movements; difficult bowel movements, jaundice, poor feeding, progressive abdominal distention and tight anal sphincter with an empty rectum. Older children with absence of soiling or overflow incontinence, chronic progressive constipation, usually with onset in infancy, failure to thrive, fecal impaction, malnutrition and progressive abdominal distention.


Official Gene Symbol OMIM ID
EDNRB 131244
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hirschsprung Disease 2 AD 600155
Waardenburg Syndrome, Type 4A AR, AD 277580

Related Test

Waardenburg Syndrome Type IVA via the EDNRB Gene


  • 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, et al. 2008. Hirschsprung disease, associated syndromes and genetics: a review. J. Med. Genet. 45: 1–14. PubMed ID: 17965226
  • Badner JA, Sieber WK, Garver KL, Chakravarti A. 1990. A genetic study of Hirschsprung disease. American journal of human genetics 46: 568. PubMed ID: 2309705
  • Kessmann J. 2006. Hirschsprung’s disease: diagnosis and management. Surgery 100: 6. PubMed ID: 17087425
  • Lipson AH, Harvey J, Oley CA. 1990. Three-generation transmission of Hirschsprung’s disease. Clin. Genet. 37: 235. PubMed ID: 2323095
  • Parisi MA, Kapur RP. 2000. Genetics of Hirschsprung disease. Curr. Opin. Pediatr. 12: 610–617. PubMed ID: 11106284
  • Parisi MA. 2011. Hirschsprung Disease Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301612


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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