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RET gene is a major risk factor for Hirschsprung's disease: a meta-analysis.
Pediatr Surg Int. 2015 Aug; 31(8):701-10.PS

Abstract

PURPOSE

During the past two decades several genes have been identified that control morphogenesis and differentiation of the enteric neuron system (ENS). These genes, when mutated or deleted, interfere with ENS development. RET gene is the major gene causing Hirschsprung's disease (HD). Mutations in RET gene are responsible for 50% of familial HD cases and 15-20% of sporadic cases. The aim of this meta-analysis was to determine the incidence of RET gene mutations in patients with HD and to correlate RET mutations with the extent of aganglionosis.

METHODS

A systematic literature-based search for relevant cohorts was performed using the terms "Hirschsprung's disease AND RET Proto-oncogene", "Hirschsprung's disease AND genetic polymorphism" and "RET Gene". The relevant cohorts of HD were systematically searched for reported mutations in the RET gene (RET+). Data on mutation site, phenotype, and familial or sporadic cases were extracted. Combined odds ratio (OR) with 95% CI was calculated to estimate the strength of the different associations.

RESULTS

In total, 23 studies concerning RET with 1270 individuals affected with HD were included in this study. 228 (18%) of these HDs were RET+. Of these 228, 96 (42%) presented as rectosigmoid, 81 (36%) long segment, 18 (8%) as TCA, 16 (7%) as total intestinal aganglionosis and 17 (7%) individuals were RET+ but no extent of aganglionosis was not reported. In the rectosigmoid group, no significant association between phenotype and RET mutation could be shown (P = 0.006), whereas a clear association could be shown between long-segment disease, total colonic- and total intestinal aganglionosis and RET mutations (P = 0.0002). Mutations most often occurred in Exon 13 (24) and showed significant association with rectosigmoid disease (P = 0.004). No significance could be shown between RET+ and sporadic cases (P = 0.53), albeit a trend towards RET+ and Familial cases could be observed (P = 0.38).

CONCLUSIONS

The association with the RET gene and HD is well recognized. This study showed a clear association between RET+ mutations and the long-segment, total colonic- and total intestinal aganglionosis. Exon 13 appears to be a mutational "hot spot" in rectosigmoid disease.

Authors+Show Affiliations

National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.No affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis

Language

eng

PubMed ID

26164711

Citation

Tomuschat, C, and P Puri. "RET Gene Is a Major Risk Factor for Hirschsprung's Disease: a Meta-analysis." Pediatric Surgery International, vol. 31, no. 8, 2015, pp. 701-10.
Tomuschat C, Puri P. RET gene is a major risk factor for Hirschsprung's disease: a meta-analysis. Pediatr Surg Int. 2015;31(8):701-10.
Tomuschat, C., & Puri, P. (2015). RET gene is a major risk factor for Hirschsprung's disease: a meta-analysis. Pediatric Surgery International, 31(8), 701-10. https://doi.org/10.1007/s00383-015-3731-y
Tomuschat C, Puri P. RET Gene Is a Major Risk Factor for Hirschsprung's Disease: a Meta-analysis. Pediatr Surg Int. 2015;31(8):701-10. PubMed PMID: 26164711.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RET gene is a major risk factor for Hirschsprung's disease: a meta-analysis. AU - Tomuschat,C, AU - Puri,P, Y1 - 2015/07/12/ PY - 2015/06/23/accepted PY - 2015/7/13/entrez PY - 2015/7/15/pubmed PY - 2016/6/9/medline SP - 701 EP - 10 JF - Pediatric surgery international JO - Pediatr Surg Int VL - 31 IS - 8 N2 - PURPOSE: During the past two decades several genes have been identified that control morphogenesis and differentiation of the enteric neuron system (ENS). These genes, when mutated or deleted, interfere with ENS development. RET gene is the major gene causing Hirschsprung's disease (HD). Mutations in RET gene are responsible for 50% of familial HD cases and 15-20% of sporadic cases. The aim of this meta-analysis was to determine the incidence of RET gene mutations in patients with HD and to correlate RET mutations with the extent of aganglionosis. METHODS: A systematic literature-based search for relevant cohorts was performed using the terms "Hirschsprung's disease AND RET Proto-oncogene", "Hirschsprung's disease AND genetic polymorphism" and "RET Gene". The relevant cohorts of HD were systematically searched for reported mutations in the RET gene (RET+). Data on mutation site, phenotype, and familial or sporadic cases were extracted. Combined odds ratio (OR) with 95% CI was calculated to estimate the strength of the different associations. RESULTS: In total, 23 studies concerning RET with 1270 individuals affected with HD were included in this study. 228 (18%) of these HDs were RET+. Of these 228, 96 (42%) presented as rectosigmoid, 81 (36%) long segment, 18 (8%) as TCA, 16 (7%) as total intestinal aganglionosis and 17 (7%) individuals were RET+ but no extent of aganglionosis was not reported. In the rectosigmoid group, no significant association between phenotype and RET mutation could be shown (P = 0.006), whereas a clear association could be shown between long-segment disease, total colonic- and total intestinal aganglionosis and RET mutations (P = 0.0002). Mutations most often occurred in Exon 13 (24) and showed significant association with rectosigmoid disease (P = 0.004). No significance could be shown between RET+ and sporadic cases (P = 0.53), albeit a trend towards RET+ and Familial cases could be observed (P = 0.38). CONCLUSIONS: The association with the RET gene and HD is well recognized. This study showed a clear association between RET+ mutations and the long-segment, total colonic- and total intestinal aganglionosis. Exon 13 appears to be a mutational "hot spot" in rectosigmoid disease. SN - 1437-9813 UR - https://www.unboundmedicine.com/medline/citation/26164711/RET_gene_is_a_major_risk_factor_for_Hirschsprung's_disease:_a_meta_analysis_ L2 - https://doi.org/10.1007/s00383-015-3731-y DB - PRIME DP - Unbound Medicine ER -