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Hirschsprung Disease via the NRTN 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
NRTN 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9109NRTN81479 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.

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), aka congenital intestinal aganglionosis, is a birth defect characterized by complete absence of neuronal ganglion cells from a portion of the intestinal tract (Eng and Mulligan 1997). In 80% of individuals aganglionosis is restricted to the rectosigmoid colon (S-HSCR); in 15%-20% aganglionosis extends beyond the sigmoid colon (L-HSCR); and in about 5% aganglionosis is present in the entire large intestine (total colonic aganglionosis) (Amiel et al. 2008). HSCR is the main genetic cause of functional intestinal obstruction in infants and children.

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, 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).


HSCR (non-syndromic) is an autosomal dominant disease. It is mainly caused by pathogenic variants in the RET gene, but other genes have been connected with the disease. The NRTN gene for instance has been reported to be involved with HSCR. It encodes a neurotrophic factor, neurturin, belonging to the TGF-beta subfamily. Neurturin signals through the RET and GPI-linked coreceptors and promotes the survival and differentiation of neurons. A NRTN mutation that was previously observed in a individual with HSCR was not sufficient to cause disease, but when, and only when, a RET mutation was present did family members have HSCR (Doray et al. 1998). However, recently three other variants (two found on the same allele in the same patient) were found in two individuals with Hirschsprung disease (Ruiz-Ferrer et al. 2011). These individuals also did not have any pathogenic variants in the RET gene or other HSCR associated genes, nor were the NRTN variants found in controls. In addition, one of these variants was shown in vitro to reduce RET phosphorylation levels, which could lead to downstream defects in the proliferation, migration, and/or differentiation of neural crest cells leading to HSCR.

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity for this gene in HSCR is currently unknown due to the limited number of studies. Analytical sensitivity should be high as the two reported missense mutations are detectable by sequencing (Human Gene Mutation Database).

Testing Strategy

This test provides full coverage of all coding exons of the NRTN 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 demonstrations 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.

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
NRTN 602018
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hirschsprung Disease 1 142623


  • 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
  • Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M, Attié T, Bachy B, Munnich A, Lyonnet S. 1998. Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum. Mol. Genet. 7: 1449–1452. PubMed ID: 9700200
  • Eng C, Mulligan LM. 1997. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. Hum. Mutat. 9: 97–109. PubMed ID: 9067749
  • Human Gene Mutation Database (Bio-base).
  • Kessmann J. 2006. Hirschsprung’s disease: diagnosis and management. Surgery 100: 6. PubMed ID: 17087425
  • 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
  • Ruiz-Ferrer M, Torroglosa A, Luzón-Toro B, Fernández RM, Antiñolo G, Mulligan LM, Borrego S. 2011. Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung’s disease. Journal of Molecular Medicine 89: 471–480. PubMed ID: 21206993


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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