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Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus.
J Med Genet. 1994 Aug; 31(8):602-6.JM

Abstract

Hirschsprung's disease (aganglionic megacolon, HSCR) is a frequent condition of unknown origin (1/5000 live births) resulting in intestinal obstruction in neonates and severe constipation in infants and adults. In the majority of cases (80%), the aganglionic tract involves the rectum and the sigmoid colon only (short segment HSCR), while in 20% of cases it extends toward the proximal end of the colon (long segment HSCR). In a previous study, we mapped a gene for long segment familial HSCR to the proximal long arm of chromosome 10 (10q11.2). Further linkage analyses in familial HSCR have suggested tight linkage of the disease gene to the RET protoncogene mapped to chromosome 10q11.2. Recently, nonsense and missense mutations of RET have been identified in HSCR patients. However, the question of whether mutations of the RET gene account for both long segment and short segment familial HSCR remained unanswered. We have performed genetic linkage analyses in 11 long segment HSCR families and eight short segment HSCR families using microsatellite DNA markers of chromosome 10q. In both anatomical forms, tight pairwise linkage with no recombinant events was observed between the RET proto-oncogene locus and the disease locus (Zmax = 2.16 and Zmax = 5.38 for short segment and long segment HSCR respectively at 0 = 0%) Multipoint linkage analyses performed in the two groups showed that the maximum likelihood estimate was at the RET locus. Moreover, we show that point mutations of the RET proto-oncogene occur either in long segment or in short segment HSCR families and we provide evidence for incomplete penetrance of the disease causing mutation. These data suggest that the two anatomical forms of familial HSCR, which have been separated on the basis of clinical and genetic criteria, may be regarded as the variable clinical expression of mutations at the RET locus.

Authors+Show Affiliations

Service de Génétique Médicale, Enfant INSERM U-393, Paris, France.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 available

Pub Type(s)

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

Language

eng

PubMed ID

7815416

Citation

Edery, P, et al. "Long Segment and Short Segment Familial Hirschsprung's Disease: Variable Clinical Expression at the RET Locus." Journal of Medical Genetics, vol. 31, no. 8, 1994, pp. 602-6.
Edery P, Pelet A, Mulligan LM, et al. Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus. J Med Genet. 1994;31(8):602-6.
Edery, P., Pelet, A., Mulligan, L. M., Abel, L., Attié, T., Dow, E., Bonneau, D., David, A., Flintoff, W., & Jan, D. (1994). Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus. Journal of Medical Genetics, 31(8), 602-6.
Edery P, et al. Long Segment and Short Segment Familial Hirschsprung's Disease: Variable Clinical Expression at the RET Locus. J Med Genet. 1994;31(8):602-6. PubMed PMID: 7815416.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long segment and short segment familial Hirschsprung's disease: variable clinical expression at the RET locus. A1 - Edery,P, AU - Pelet,A, AU - Mulligan,L M, AU - Abel,L, AU - Attié,T, AU - Dow,E, AU - Bonneau,D, AU - David,A, AU - Flintoff,W, AU - Jan,D, PY - 1994/8/1/pubmed PY - 1994/8/1/medline PY - 1994/8/1/entrez SP - 602 EP - 6 JF - Journal of medical genetics JO - J Med Genet VL - 31 IS - 8 N2 - Hirschsprung's disease (aganglionic megacolon, HSCR) is a frequent condition of unknown origin (1/5000 live births) resulting in intestinal obstruction in neonates and severe constipation in infants and adults. In the majority of cases (80%), the aganglionic tract involves the rectum and the sigmoid colon only (short segment HSCR), while in 20% of cases it extends toward the proximal end of the colon (long segment HSCR). In a previous study, we mapped a gene for long segment familial HSCR to the proximal long arm of chromosome 10 (10q11.2). Further linkage analyses in familial HSCR have suggested tight linkage of the disease gene to the RET protoncogene mapped to chromosome 10q11.2. Recently, nonsense and missense mutations of RET have been identified in HSCR patients. However, the question of whether mutations of the RET gene account for both long segment and short segment familial HSCR remained unanswered. We have performed genetic linkage analyses in 11 long segment HSCR families and eight short segment HSCR families using microsatellite DNA markers of chromosome 10q. In both anatomical forms, tight pairwise linkage with no recombinant events was observed between the RET proto-oncogene locus and the disease locus (Zmax = 2.16 and Zmax = 5.38 for short segment and long segment HSCR respectively at 0 = 0%) Multipoint linkage analyses performed in the two groups showed that the maximum likelihood estimate was at the RET locus. Moreover, we show that point mutations of the RET proto-oncogene occur either in long segment or in short segment HSCR families and we provide evidence for incomplete penetrance of the disease causing mutation. These data suggest that the two anatomical forms of familial HSCR, which have been separated on the basis of clinical and genetic criteria, may be regarded as the variable clinical expression of mutations at the RET locus. SN - 0022-2593 UR - https://www.unboundmedicine.com/medline/citation/7815416/Long_segment_and_short_segment_familial_Hirschsprung's_disease:_variable_clinical_expression_at_the_RET_locus_ L2 - https://jmg.bmj.com/lookup/pmidlookup?view=long&pmid=7815416 DB - PRIME DP - Unbound Medicine ER -