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


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.

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Figure 1: Transmission disequilibrium tests.
Figure 2: Identification and characterization of conserved sequence elements within 350 kb encompassing RET.
Figure 3: Identification and functional characterization of RET MCS + 9.7.
Figure 4: Worldwide allele frequencies of RET + 3.


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We thank members of the Chakravarti laboratory for their discussions on this manuscript, M. Kenton for assistance with family recruitment, and E. Margulies and M. Blanchette for help with multi-species sequence analysis. We thank the NISC Comparative Sequencing Program for generating the multi-species sequence data. We also acknowledge the many participants of the NISC Comparative Sequencing Program, especially the leadership provided by G. Bouffard and B. Blakesley. We also acknowledge the many participants of the NISC Comparative Sequencing Program, especially the leadership provided by G. Bouffard and B. Blakesley. This work was supported by grants from the US National Institute of Child Health and Development.

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Correspondence to Aravinda Chakravarti.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Table S1

Positions of all identified MCSs. Nucleotide positions are given on human chromosome 10 relative to build 34 (July 2003) of the genome. (XLS 22 kb)

Supplementary Table S2

Predicted transcription factor binding sites in MCS+9.7. TRANSFAC predictions of putative transcription factor binding sites given with reference to build 34 of the human genome. (XLS 28 kb)

Supplementary Table S3

Haplotype frequencies in Africa, Asia, Europe and HSCR cases. PHASE was used to reconstruct haplotypes in the 5′ region of RET. (XLS 20 kb)

Supplementary Figure S1

Multi-species alignment showing the position of RET+3 within the context of MCS+9.7. (PDF 20 kb)

Supplementary Methods

Additional methodological details are provided in this file. (DOC 44 kb)

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Emison, E., McCallion, A., Kashuk, C. et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434, 857–863 (2005).

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