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Recent research on some "single-gene" diseases has begun to shed light on the complexity of the relationship between genotype and phenotype. Hirschsprung disease is a rare congenital disorder in which part of the rectum or colon lacks nerve cells, affecting bowel motility and resulting in severe constipation and bowel obstruction. The disease shows variable phenotype, for example some patients lack nerve cells in the rectum (short-segment disease) while in some a much larger segment of the colon is involved (long-segment disease). Mutations in any of several different genes have been shown to cause the disease. In some patients, disease is associated with loss-of-function mutations in the RET proto-oncogene and there is evidence that polymorphisms in this same gene (that is, genetic variants also found in normal individuals) can affect the phenotype of Hirschsprung patients. Fitze et al have analysed the relationship between RET mutations and polymorphisms and the disease phenotype in 76 patients with Hirschsprung’s disease [Fitze, G. et al (2002) Lancet 359, 1200-1205]. They found evidence that the disease phenotype is affected both by variants in different genes and between interactions between genetic variants in the same gene. For example, they found that the 18 patients who had RET mutations were significantly more likely to have the long-segment phenotype than those without RET mutations. In addition, patients homozygous for the AA form of the c135G/A polymorphism in the RET gene were much less likely to have RET mutations than those with the GA or GG genotypes. Moreover, in patients with the long-segment phenotype who had a RET mutation and the GA genotype, the RET mutation was usually on the same chromosome as the G allele, suggesting that these variants might interact to affect the expression of the gene.

Comment: The results of this study, which are also discussed in the accompanying editorial by McCabe, illustrate modes of genetic interaction, and ways in which these interactions can affect phenotype, that are likely also to be relevant to the pathogenesis of common polygenic disease such as coronary heart disease.