Nature Genetics
31, 89 - 93 (2002)
Published online: 15 April 2002; | doi:10.1038/ng868
Segregation at three loci explains familial and population risk in Hirschsprung diseaseStacey Bolk Gabriel1, 4, 5, Rémi Salomon2, 5, Anna Pelet2, Misha Angrist1, Jeanne Amiel2, Myriam Fornage1, 4, Tania Attié-Bitach2, Jane M. Olson1, Robert Hofstra3, Charles Buys3, Julie Steffann2, Arnold Munnich2, Stanislas Lyonnet2
& Aravinda Chakravarti11
Department of Genetics and Center for Human Genetics, Department of Epidemiology and Biostatistics (Metro Health Campus), Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA. 2
Department of Genetics and INSERM U-393, Hospital Necker-Enfants Malades, Paris, France. 3
Department of Medical Genetics, University of Groningen, Groningen, The Netherlands. 4
Present addresses: Whitehead Institute Center for Genome Research, Cambridge, Massachusetts, USA (S.B.G.); University of Texas, Institute of Molecular Medicine, Houston, Texas, USA (M.F.). 5
These authors contributed equally to this work.
Correspondence should be addressed to Aravinda Chakravarti aravinda@jhmi.eduHirschsprung 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.
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