Hirschsprung Disease (Non-syndromic) Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10225 ECE1 81479,81479 Order Options and Pricing
EDN3 81479,81479
EDNRB 81479,81479
GDNF 81479,81479
NRTN 81479,81479
RET 81406,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10225Genes x (6)81479 81406, 81479 $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

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

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

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 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).

Genetics

HSCR (non-syndromic) is caused by mutations in at least six genes: RET, EDN3, EDNRB, GDNF, NRTN and ECE1 (Parisi and Kapur 2000). Mutations in RET alone account for 7-41% of all HSCR cases (Sancandi et al. 2000), while EDNRB (Kusafuka et al. 1996) and EDN3 (Svensson et al. 1999) mutations account for approximately 10% of individuals with HSCR. Mutations in GDNF and NRTN have been identified in only a small minority of individuals with HSCR. Mutations in ECE1 are extremely rare and have been reported in only one individual, who also had craniofacial anomalies and a heart defect (Hofstra et al 1999).

RET: Causative for HSCR1 and occurs due to heterozygous missense and truncating mutations, suggesting an autosomal dominant mode of inheritance. RET protein is essential for the normal development of several kinds of nerve cells, including nerves in the intestine (enteric neurons). Loss of function of RET leads to improper development of enteric nerves, resulting in severe constipation or blockage of the intestine. L-HSCR and S-HSCR are regarded as the variable clinical expression of mutations at the RET locus. Mutations in RET are also involved in syndromic HSCR - Congenital Central Hypoventilation Syndrome (CCHS) as well as Multiple Endocrine Neoplasia II and Pheochromocytoma.

EDNRB: Causative for HSCR2, mostly due to missense and truncating mutations. Can be inherited as autosomal dominant or recessive. The protein encoded, endothelin receptor type B, is 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.

GDNF: Causative for HSCR3 due to heterozygous missense mutations, suggesting an autosomal dominant mode of inheritance. GDNF is a highly conserved neurotropic factor that promotes the survival and differentiation of dopaminergic neurons. GDNF protein functions as a ligand for the RET proto-oncogene, and therefore loss of function mutations in the gene (missense or nonsense) impacts ligand binding resulting in disease. Mutations in GDNF are also associated with syndromic HSCR - Congenital Central Hypoventilation Syndrome (CCHS).

EDN3: Causative for HSCR4, due to missense and truncating mutations. Can be inherited as autosomal dominant or recessive. EDN3 protein (endothelin 3) functions by interacting with the endothelin receptor type B. Together they play an important role in neural crest cells and pigment-producing cells called melanocytes. Disruption or loss of endothelin 3 results in the loss of enteric nerve cells that are critical to intestinal development, resulting in Hirschsprung disease. Mutations in EDN3 are also associated with syndromic HSCR - Waardenburg-Shah syndrome.

ECE1: Causative for Hirschsprung Disease, Cardiac Defects and Autonomic Dysfunction. Heterozygous mutations in ECE1 though extremely rare, suggest an autosomal dominant mode of inheritance (Hofstra et al. 1999). ECE1 encoded protein, endothelin convertin enzyme-1, is involved in proteolytic processing of endothelin precursors to biologically active peptides. Disruption or loss of the ECE1 protein results in disease. Mutations in ECE1 are also associated with Essential Hypertension.

NRTN: Causative for Hirschsprung Disease. 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 an 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

Mutations in RET alone account for 7-41% of all HSCR cases (Sancandi et al. 2000), while EDNRB (Kusafuka et al. 1996) and EDN3 (Svensson et al. 1999) mutations account for approximately 10% of individuals with HSCR. Mutations in GDNF and NRTN have been identified in only a small minority of individuals with HSCR. Mutations in ECE1 are extremely rare and have been reported in only one individual, who also had craniofacial anomalies and a heart defect (Hofstra et al 1999).

The clinical sensitivity of gross deletions in the RET gene in Hirschsprung disease is currently unknown. However, the whole RET gene has previously been observed to deleted and associated with HSCR (Yin et al. 1996).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

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.

Genes

Official Gene Symbol OMIM ID
ECE1 600423
EDN3 131242
EDNRB 131244
GDNF 600837
NRTN 602018
RET 164761
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • 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
  • Hofstra RM, Valdenaire O, Arch E, Osinga J, Kroes H, Loffler BM, Hamosh A, Meijers C, Buys CH. 1999. A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. Am J Hum Genet 64: 304–308. PubMed ID: 9915973
  • Kessmann J. 2006. Hirschsprung’s disease: diagnosis and management. Surgery 100: 6. PubMed ID: 17087425
  • Kusafuka T, Wang Y, Puri P. 1996. Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung’s disease. Hum. Mol. Genet. 5: 347–349. PubMed ID: 8852658
  • 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
  • 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
  • Sancandi M, Ceccherini I, Costa M, Fava M, Chen B, Wu Y, Hofstra R, Laurie T, Griffths M, Burge D, Tam PK. 2000. Incidence of RET mutations in patients with Hirschsprung’s disease. J. Pediatr. Surg. 35: 139–142; discussion 142–143. PubMed ID: 10646792
  • Svensson PJ, Tell D Von, Molander ML, Anvret M, Nordenskjöld A. 1999. A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung’s disease. Pediatr. Res. 45: 714–717. PubMed ID: 10231870
  • Yin L, Seri M, Barone V, Tocco T, Scaranari M, Romeo G. 1996. Prevalence and parental origin of de novo RET mutations in Hirschsprung’s disease. Eur. J. Hum. Genet. 4: 356–358. PubMed ID: 9043870

Ordering/Specimens

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.

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  • Billing information along with specimen and shipping instructions are within the requisition form.
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