Segregation at three loci explains familial and population risk in Hirschsprung disease.

The paper explains the genetic contribution to the short-segment form of Hirschsprung disease (S-HSCR), which is a complex genetic disorder, by the interaction of three genes. The inheritance of S-HSCR can be explained by a multiplicative model involving the RET gene and two others, so far unidentified, which map to 3p21 and 19q12. This paper is not only exceptionally clearly written but also breaks new ground in the analysis of the genetics of disorders with non Mendelian inheritance but a strong genetic component.

This brilliant paper outlines the complete genetic dissection of a complex trait, Hirschsprung disease. The authors show that modifier loci may be discovered not only by controlling for the presence of mutation at a particular locus but also by the 'severity' or type of the polymorphism present there. Additionally, relatively frequent diverse or recurrent noncoding polymorphisms in the RET gene may represent low-penetrance alleles.

This paper identifies three loci that confer major predisposition to short segment Hirschsprung disease (HSCR) and proposes a simple multiplicative model to account for differences between genotypes in the relative risk of developing the disorder. Of the three loci, one at 10q11 is previously known (RET), the other two, at 3p21 and 19q12, are novel and do not correspond to known HSCR loci. This work provides an elegant exemplar of how to model genotypic risk in an oligogenic disorder; but it should be noted that the same data were used for the original linkage and the subsequent modelling, so that an independent cohort will be required to test the model's validity.