title: Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease.
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.affiliation: Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. basel@post.tau.ac.il
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.forename: Zvi
authors.initials: Z
authors.lastname: Steiner
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Yoram
authors.initials: Y
authors.lastname: Rozenbach
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
mesh_terms: D000483:Alleles; D018912:Arabs / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D007557:Israel; D008297:Male; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret