Segregation at three loci explains familial and population risk in Hirschsprung disease.
Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence. The gene at 10q11 is probably RET, supporting its crucial role in all forms of HSCR; however, coding sequence mutations are present in only 40% of linked families, suggesting the importance of noncoding variation. Here we show oligogenic inheritance of S-HSCR, the 3p21 and 19q12 loci as RET-dependent modifiers, and a parent-of-origin effect at RET. This study demonstrates by a complete genetic dissection why the inheritance pattern of S-HSCR is nonmendelian.
Duke Scholars
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Related Subject Headings
- Risk Factors
- Receptor Protein-Tyrosine Kinases
- Proto-Oncogene Proteins c-ret
- Proto-Oncogene Proteins
- Models, Genetic
- Male
- Humans
- Hirschsprung Disease
- Glial Cell Line-Derived Neurotrophic Factor Receptors
- Genetic Markers
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Risk Factors
- Receptor Protein-Tyrosine Kinases
- Proto-Oncogene Proteins c-ret
- Proto-Oncogene Proteins
- Models, Genetic
- Male
- Humans
- Hirschsprung Disease
- Glial Cell Line-Derived Neurotrophic Factor Receptors
- Genetic Markers