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Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease.
Eur J Hum Genet. 2007 Feb; 15(2):242-5.EJ

Abstract

Hirschsprung disease (HSCR) is characterised by intestinal obstruction resulting from an absence of ganglion cells in the intestinal tract. The mutations in the major gene, RET, associated with isolated HSCR, are dominant loss-of-function mutations with incomplete penetrance and variable expressivity. We have ascertained a large inbred Israeli-Arab family segregating HSCR. Sequencing of the RET gene showed a splicing mutation, IVS6+5G- >A, in the homozygous state in all the females with severe forms of HSCR and in the heterozygous state in the male patient with short-segment HSCR. The recently described hypomorphic-RET predisposing allele, rs2435357, was transmitted in the heterozygous state to the male patient, but was not transmitted to the three affected females. Although the heterozygous IVS6+5G- >A is of low-penetrance for short-segment HSCR disease, the homozygous state is fully penetrant for total aganglionosis or long-segment HSCR. As in other inbred populations segregating a weakly penetrant RET allele (Mennonite), our findings support the hypothesis that the penetrance of RET gene mutations for the HSCR phenotype depends on: (i) the nature of the mutation, (ii) the allele dosage and (iii) modifier-loci.

Authors+Show Affiliations

Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. basel@post.tau.ac.ilNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17091122

Citation

Basel-Vanagaite, Lina, et al. "Allele Dosage-dependent Penetrance of RET Proto-oncogene in an Israeli-Arab Inbred Family Segregating Hirschsprung Disease." European Journal of Human Genetics : EJHG, vol. 15, no. 2, 2007, pp. 242-5.
Basel-Vanagaite L, Pelet A, Steiner Z, et al. Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease. Eur J Hum Genet. 2007;15(2):242-5.
Basel-Vanagaite, L., Pelet, A., Steiner, Z., Munnich, A., Rozenbach, Y., Shohat, M., & Lyonnet, S. (2007). Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease. European Journal of Human Genetics : EJHG, 15(2), 242-5.
Basel-Vanagaite L, et al. Allele Dosage-dependent Penetrance of RET Proto-oncogene in an Israeli-Arab Inbred Family Segregating Hirschsprung Disease. Eur J Hum Genet. 2007;15(2):242-5. PubMed PMID: 17091122.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease. AU - Basel-Vanagaite,Lina, AU - Pelet,Anna, AU - Steiner,Zvi, AU - Munnich,Arnold, AU - Rozenbach,Yoram, AU - Shohat,Mordechai, AU - Lyonnet,Stanislas, Y1 - 2006/11/08/ PY - 2006/11/9/pubmed PY - 2007/3/17/medline PY - 2006/11/9/entrez SP - 242 EP - 5 JF - European journal of human genetics : EJHG JO - Eur J Hum Genet VL - 15 IS - 2 N2 - Hirschsprung disease (HSCR) is characterised by intestinal obstruction resulting from an absence of ganglion cells in the intestinal tract. The mutations in the major gene, RET, associated with isolated HSCR, are dominant loss-of-function mutations with incomplete penetrance and variable expressivity. We have ascertained a large inbred Israeli-Arab family segregating HSCR. Sequencing of the RET gene showed a splicing mutation, IVS6+5G- >A, in the homozygous state in all the females with severe forms of HSCR and in the heterozygous state in the male patient with short-segment HSCR. The recently described hypomorphic-RET predisposing allele, rs2435357, was transmitted in the heterozygous state to the male patient, but was not transmitted to the three affected females. Although the heterozygous IVS6+5G- >A is of low-penetrance for short-segment HSCR disease, the homozygous state is fully penetrant for total aganglionosis or long-segment HSCR. As in other inbred populations segregating a weakly penetrant RET allele (Mennonite), our findings support the hypothesis that the penetrance of RET gene mutations for the HSCR phenotype depends on: (i) the nature of the mutation, (ii) the allele dosage and (iii) modifier-loci. SN - 1018-4813 UR - https://www.unboundmedicine.com/medline/citation/17091122/Allele_dosage_dependent_penetrance_of_RET_proto_oncogene_in_an_Israeli_Arab_inbred_family_segregating_Hirschsprung_disease_ DB - PRIME DP - Unbound Medicine ER -