A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk
作者： Eileen Sproat Emison , Andrew S. McCallion , Carl S. Kashuk , Richard T. Bush , Elizabeth Grice
DOI: 10.1038/NATURE03467
关键词:
摘要: The identification of common variants that contribute to the genesis human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations receptor tyrosine kinase RET risk combination with at other genes. We have used family-based association studies identify interval, and integrated this comparative functional genomic analysis prioritize conserved elements within can be sought. now show non-coding variant enhancer-like intron 1 significantly associated HSCR susceptibility makes 20-fold greater contribution than alleles do. This mutation reduces vitro enhancer activity markedly, has low penetrance, different genetic effects males females, explains several features complex inheritance pattern HSCR. Thus, low-penetrance variants, identified by studies, underlie both diseases.
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