RET-Related Hirschsprung Disease
Hirschsprung Disease (HSCR) is multigenic congenital disease of the large intestine characterized by absence of neuronal ganglia, colon enlargement, and constipation.
PrintHirschsprung Disease (HSCR) is multigenic congenital disease of the large intestine characterized by absence of neuronal ganglia, colon enlargement, and constipation.
It is typically suspected in newborns who have not passed meconium within 48 hours after birth. Multiple congenital abnormalities are present in approximately 30% of patients.
HSCR is associated with mutations in eight partially-interdependent genes, with mutations occurring primarily in the RET gene. Dominant loss-of-function mutations in RET have been identified in 50% of familial and 35% of sporadic cases. RET has also been shown to act as a modifier gene in other syndromic forms of Hirschsprung Disease.
In the Ambry Test: RET-Related Hirschsprung Disease, RET exons 2, 3, 5, 6, 9, 10, 12, 13, and 17 are analyzed first. If a disease causing mutation is not identified, the remainder of the 20 exons are analyzed.
Hirschsprung disease (HSCR) is multigenic congenital disease of the large intestine characterized by absence of neuronal ganglia, colon enlargement, and constipation; it is typically suspected in newborns who have not passed meconium 48 hours after birth.1 Hirschsprung disease has an estimated incidence of one out of 5,000 births, varying almost two-fold depending upon ethnicity, with males being four times more likely affected than females.2,3 HSRC has been associated with two phenotypes: short segment (S-HSCR or Type I HSCR) and long segment (L-HSCR or Type II HSCR). S-HSCR accounts for 60%-85% of patients and affects the rectum along with a small portion of the colon (the sigmoid). The remaining 15%-25% of patients have L-HSCR which also affects the rectum and extends beyond the upper sigmoid.1,4 HSCR is associated with multiple congenital abnormalities in approximately 30% of patients.4 X-ray, barium enema studies, and rectal manometry can be helpful in establishing diagnosis of HSCR, but confirmation requires a rectal biopsy.1,5
HSCR is associated with mutations in eight partially-interdependent genes, with mutations occurring primarily in the RET gene. Dominant loss-of-function mutations in RET have been identified in 50% of familial and 35% of sporadic HSCR cases.6 RET has also been shown to act as a modifier gene in other syndromic forms of HSCR.7
Diagnostic genetic testing is helpful for individuals known or suspected to have Hirschsprung disease especially those with L-HSCR. Testing is available for relatives of HSCR patients in whom the mutation is known and for pregnancies at risk.
RET exons 2, 3, 5, 6, 9, 10, 12, 13, and 17 plus at least 20 bases into the 5’ and 3’ ends of all the introns are analyzed. If a disease causing mutation is not identified, the remainder of the 20 exons of RET plus at least 20 bases into the 5’ and 3’ ends of all the introns will be analyzed. Specific mutation analysis for individual RET mutations known to be in the family is also available.
Mutations in the RET gene account for 50% of familial cases of HSCR and up to 35% of sporadic cases.8 The Ambry Test: RET-Related Hirschsprung Disease is capable of detecting >99% of described mutations in RET.
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self-Collection container. Store and ship at room temperature.
DNA: Send 20 μg in TE at 50-100 ng/μl. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.
| Test Code | Technique | CPT Codes |
|---|---|---|
| 2700 | RET Gene Sequence Analysis Reflex Option | 83891x1, 83894x21, 83898x20, 83904x35, 83909x35, 83912x1 |
| 2708 | RET Gene Sequence Analysis Concurrent | 83891x1, 83894x21, 83898x20, 83904x35, 83909x35, 83912x1 |
| 2704 | RET Partial Sequence Analysis - Step 1 only | 83891x1, 83894x10, 83898x9, 83904x18, 83909x18, 83912x1 |
| Technique | Days |
|---|---|
| RET Gene Sequence Analysis Reflex Option | 7-28 |
| RET Gene Sequence Analysis Concurrent | 10-21 |
| RET Partial Sequence Analysis - Step 1 only | 7-14 |
1 Amiel J, Lyonnet S. J Med Genet. 2001 Nov;38(11):729-39.
2 Badner JA et al. Am J Hum Genet. 1990 Mar;46(3):568-80.
3 Chin TW et al. J Chin Med Assoc. 2008 Aug;71(8):406-10.
4 Passarge E. Nat Genet. 2002 May;31(1):11-2.
5 Neville H. (2008) Hirschsprung Disease. eMedicine. http://emedicine.medscape.com/article/929733-diagnosis. Accessed October 12, 2009.
6 Bolk S et al. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):268-73.
7 Pontual L et al. J Med Genet. 2006;43:419-423.
8 Tam et al. Pediatr Surg Int. 2009;25:543-558