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The Letter to JMG titled, Ancestral RET haplotype associated with Hirschsprung’s disease shows linkage disequilibrium at – 1249 (J Med Genet 2005;42:322–27) should have been published as a short report and the following abstract was omitted:

Background: Hirschsprung disease (HSCR) is a complex disorder with traditional germline mutations in RET in up to 30% of familial cases and in 3% of sporadic cases in a population-based series. We have previously demonstrated that an ancestral haplotype at the 5’ end of RET (haplotype 0) was strongly associated with a large subset of isolated HSCR cases and that a putative low penetrance susceptibility locus was encompassed within this ancestral haplotype, anchored by exon 2 SNP A45A.

Objective: To determine the 5’ extent of the HSCR-associated ancestral haplotype by defining the linkage disequilibrium breakpoint in search for the low penetrance susceptibility locus.

Methods: Systematic screening of the region upstream of the anchoring A45A SNP, comprising RET intron 1, exon 1, and promoter in 117 population-based HSCR cases and 100 controls. Dual luciferase assay to determine differential activities between SNP combinations near a transcription start site.

Results: New SNP’s were found which formed upstream haplotypes, anchored by A45A, in linkage disequilibrium with HSCR (χ2 =  76.96, p<0.00000001). Linkage disequilibrium appeared to break at the –1249C/T SNP. Further, the HSCR-associated genotype (00) was found in >60% of HSCR but only 2% of controls. Because only 2 variants, -200A>G and –196C>A, lie within the promoter region and are in proximity to the transcriptional start site (at –195), we modelled these combinations into constructs for luciferase reporter assay. The HSCR-associated SNP combination showed the lowest activity and the control-associated combination, the highest.

Conclusions: Our observations seem to discard the existence of a HSCR-causing mutation as it is conceived in the traditional sense, but strengthen the idea of a specific combination of variants conferring susceptibility to the disease in a low penetrance fashion. The data derived from our functional "in vitro" studies would suggest that the HSCR-associated haplotype 0 may result in a lower level of expression of the RET gene.

The journal apologises for this error.

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