A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk

Eileen Sproat Emison, Andrew S. McCallion, Carl S. Kashuk, Richard T. Bush, Elizabeth Grice, Shin Lin, Matthew E. Portnoy, David J. Cutler, Eric D. Green and Aravinda Chakravarti ()
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Eileen Sproat Emison: Johns Hopkins University School of Medicine
Andrew S. McCallion: Johns Hopkins University School of Medicine
Carl S. Kashuk: Johns Hopkins University School of Medicine
Richard T. Bush: Johns Hopkins University School of Medicine
Elizabeth Grice: Johns Hopkins University School of Medicine
Shin Lin: Johns Hopkins University School of Medicine
Matthew E. Portnoy: Genome Technology Branch
David J. Cutler: Johns Hopkins University School of Medicine
Eric D. Green: Genome Technology Branch
Aravinda Chakravarti: Johns Hopkins University School of Medicine

Nature, 2005, vol. 434, issue 7035, 857-863

Abstract: Abstract The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.

Date: 2005
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DOI: 10.1038/nature03467

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