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

Author

Listed:
  • 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
    National Institutes of Health)

  • Aravinda Chakravarti

    (Johns Hopkins University School of Medicine)

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.

Suggested Citation

  • 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 & Aravinda Chakravarti, 2005. "A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk," Nature, Nature, vol. 434(7035), pages 857-863, April.
  • Handle: RePEc:nat:nature:v:434:y:2005:i:7035:d:10.1038_nature03467
    DOI: 10.1038/nature03467
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