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Incidence of RET mutations in patients with Hirschsprung's disease.
J Pediatr Surg. 2000 Jan; 35(1):139-42; discussion 142-3.JP

Abstract

BACKGROUND

RET mutations have been reported variously to affect 7% to 41% of Hirschsprung's disease (HSCR) patients depending on familial or sporadic occurrence of the disease, length of aganglionosis and possible association with other disease phenotypes. The authors report a study of the incidence of RET mutations in unselected HSCR patients from two regional centers and correlate their genotypes and phenotypes.

METHODS

The records of HSCR patients treated in 2 regional centers with a combined population of 5 million were reviewed, and blood samples were obtained from 57 patients. During the same period, 39 patients with similar demographic data refused or provided insufficient blood for study. DNA was extracted, and the 21 exons of the RET protooncogene were screened for mutations using denaturing gradient gel electrophoresis (DGGE).

RESULTS

Of 57 patients, 48 were sporadic, and 9 were familial. Lengths of aganglionosis were total colonic, 4; long, 11; short, 39; ultrashort, 1; unclassified, 2. Associated anomalies were present in 20. Causative mutations were identified in 4 (7%): missense or "silent" in 3 (exons 5, 11, 13) and deletion in 1. The silent mutation of exon 11 recently has been shown to have effects on correct RET mRNA splicing. One mutation occurred in total colonic aganglionosis (25%), 1 in long segment dysganglionosis (9%), and 2 in short segment aganglionosis (5%). Surprisingly, all these mutations occurred in sporadic cases (10%). Five patients (9%) had rare polymorphic alleles at exon 14 (n = 1) and exon 18 (n = 4). Fifty patients (88%) showed common polymorphic alleles (sequence variants) in 1 or more exons (> 4, n = 5).

CONCLUSIONS

RET mutation as a primary cause for Hirschsprung's disease in the general surgical population is less frequent than previously thought. This observation is compatible with the hypothesis that HSCR could be a polygenic disease caused by additive subclinical effects of more than one gene, including RET.

Authors+Show Affiliations

Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, SAR, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10646792

Citation

Sancandi, M, et al. "Incidence of RET Mutations in Patients With Hirschsprung's Disease." Journal of Pediatric Surgery, vol. 35, no. 1, 2000, pp. 139-42; discussion 142-3.
Sancandi M, Ceccherini I, Costa M, et al. Incidence of RET mutations in patients with Hirschsprung's disease. J Pediatr Surg. 2000;35(1):139-42; discussion 142-3.
Sancandi, M., Ceccherini, I., Costa, M., Fava, M., Chen, B., Wu, Y., Hofstra, R., Laurie, T., Griffths, M., Burge, D., & Tam, P. K. (2000). Incidence of RET mutations in patients with Hirschsprung's disease. Journal of Pediatric Surgery, 35(1), 139-42; discussion 142-3.
Sancandi M, et al. Incidence of RET Mutations in Patients With Hirschsprung's Disease. J Pediatr Surg. 2000;35(1):139-42; discussion 142-3. PubMed PMID: 10646792.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Incidence of RET mutations in patients with Hirschsprung's disease. AU - Sancandi,M, AU - Ceccherini,I, AU - Costa,M, AU - Fava,M, AU - Chen,B, AU - Wu,Y, AU - Hofstra,R, AU - Laurie,T, AU - Griffths,M, AU - Burge,D, AU - Tam,P K, PY - 2000/1/26/pubmed PY - 2000/1/26/medline PY - 2000/1/26/entrez SP - 139-42; discussion 142-3 JF - Journal of pediatric surgery JO - J Pediatr Surg VL - 35 IS - 1 N2 - BACKGROUND: RET mutations have been reported variously to affect 7% to 41% of Hirschsprung's disease (HSCR) patients depending on familial or sporadic occurrence of the disease, length of aganglionosis and possible association with other disease phenotypes. The authors report a study of the incidence of RET mutations in unselected HSCR patients from two regional centers and correlate their genotypes and phenotypes. METHODS: The records of HSCR patients treated in 2 regional centers with a combined population of 5 million were reviewed, and blood samples were obtained from 57 patients. During the same period, 39 patients with similar demographic data refused or provided insufficient blood for study. DNA was extracted, and the 21 exons of the RET protooncogene were screened for mutations using denaturing gradient gel electrophoresis (DGGE). RESULTS: Of 57 patients, 48 were sporadic, and 9 were familial. Lengths of aganglionosis were total colonic, 4; long, 11; short, 39; ultrashort, 1; unclassified, 2. Associated anomalies were present in 20. Causative mutations were identified in 4 (7%): missense or "silent" in 3 (exons 5, 11, 13) and deletion in 1. The silent mutation of exon 11 recently has been shown to have effects on correct RET mRNA splicing. One mutation occurred in total colonic aganglionosis (25%), 1 in long segment dysganglionosis (9%), and 2 in short segment aganglionosis (5%). Surprisingly, all these mutations occurred in sporadic cases (10%). Five patients (9%) had rare polymorphic alleles at exon 14 (n = 1) and exon 18 (n = 4). Fifty patients (88%) showed common polymorphic alleles (sequence variants) in 1 or more exons (> 4, n = 5). CONCLUSIONS: RET mutation as a primary cause for Hirschsprung's disease in the general surgical population is less frequent than previously thought. This observation is compatible with the hypothesis that HSCR could be a polygenic disease caused by additive subclinical effects of more than one gene, including RET. SN - 0022-3468 UR - https://www.unboundmedicine.com/medline/citation/10646792/Incidence_of_RET_mutations_in_patients_with_Hirschsprung's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3468(00)80094-9 DB - PRIME DP - Unbound Medicine ER -