Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2
Copyright policy )Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2
Hirschsprung disease (HSCR), a congenital disorder characterized by intestinal obstruction due to absence of enteric ganglia along variable lengths of the intestinal tract, occurs both in familial and sporadic cases. RET mutations have been found in approximately 50% of the families, but explains only a minority of sporadic cases. This study aims at investigating a possible role of RET in sporadic HSCR patients. Haplotypes of 13 DNA markers, within and flanking RET, have been determined for 117 sporadic HSCR patients and their parents. Strong association was observed for six markers in the 5' region of RET. The largest distortions in allele transmission were found at the same markers. One single haplotype composed of these six markers was present in 55.6% of patients versus 16.2% of controls. Odds ratios (ORs) revealed a highly increased risk of homozygotes for this haplotype to develop HSCR (OR>20). These results allowed us to conclude that RET plays a crucial role in HSCR even when no RET mutations are found. An unknown functional disease variant(s) with a dosage-dependent effect in HSCR is likely located between the promoter region and exon 2 of RET.
- Amsterdam UMC Netherlands
- Amsterdam UMC, location AMC Netherlands
- University of Groningen Netherlands
- Erasmus University Rotterdam Netherlands
Adult, Hirschsprung disease, HAPLOTYPE, Polymorphism, Single Nucleotide, haplotype reconstruction, Linkage Disequilibrium, Gene Frequency, Humans, Genetic Predisposition to Disease, Hirschsprung Disease, Child, Promoter Regions, Genetic, SMAD INTERACTING PROTEIN-1, DNA Primers, Netherlands, RISK, Oncogene Proteins, SHAH-WAARDENBURG SYNDROME, MULTIGENIC INHERITANCE, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, GERMLINE MUTATIONS, MOUSE MODEL, ASSOCIATION, Exons, PROTOONCOGENE, HSCR, Gene Components, Haplotypes, Mutation, RET, ENDOTHELIN-3 GENE, Microsatellite Repeats
Adult, Hirschsprung disease, HAPLOTYPE, Polymorphism, Single Nucleotide, haplotype reconstruction, Linkage Disequilibrium, Gene Frequency, Humans, Genetic Predisposition to Disease, Hirschsprung Disease, Child, Promoter Regions, Genetic, SMAD INTERACTING PROTEIN-1, DNA Primers, Netherlands, RISK, Oncogene Proteins, SHAH-WAARDENBURG SYNDROME, MULTIGENIC INHERITANCE, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, GERMLINE MUTATIONS, MOUSE MODEL, ASSOCIATION, Exons, PROTOONCOGENE, HSCR, Gene Components, Haplotypes, Mutation, RET, ENDOTHELIN-3 GENE, Microsatellite Repeats
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