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.
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We are grateful to the families who participated in this study. We thank Dr Gabrielle Halpern for her help with editing the manuscript and Irit Lis for preparing the figures.
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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 15, 242–245 (2007). https://doi.org/10.1038/sj.ejhg.5201733
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DOI: https://doi.org/10.1038/sj.ejhg.5201733
