Segregation at three loci explains familial and population risk in Hirschsprung disease
- 15 April 2002
- journal article
- letter
- Published by Springer Nature in Nature Genetics
- Vol. 31 (1) , 89-93
- https://doi.org/10.1038/ng868
Abstract
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.Keywords
This publication has 23 references indexed in Scilit:
- A human model for multigenic inheritance: Phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locusProceedings of the National Academy of Sciences, 2000
- Population genetics—making sense out of sequenceNature Genetics, 1999
- Allele-Sharing Models: LOD Scores and Accurate Linkage TestsAmerican Journal of Human Genetics, 1997
- Likelihood-Based Models for Genetic Linkage Analysis Using Affected Sib PairsHuman Heredity, 1997
- The New Genomics: Global Views of BiologyScience, 1996
- Genetic dissection of complex traits: guidelines for interpreting and reporting linkage resultsNature Genetics, 1995
- Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung diseaseHuman Molecular Genetics, 1995
- A missense mutation of the endothelin-B receptor gene in multigenic hirschsprung's diseaseCell, 1994
- Genetic Dissection of Complex TraitsScience, 1994
- Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor RetNature, 1994