Identifying modifier genes of monogenic disease: strategies and difficulties

Hum Genet. 2008 Nov;124(4):357-68. doi: 10.1007/s00439-008-0560-2. Epub 2008 Sep 11.


Substantial clinical variability is observed in many Mendelian diseases, so that patients with the same mutation may develop a very severe form of disease, a mild form or show no symptoms at all. Among the factors that may explain these differences in disease expression are modifier genes. In this paper, we review the different strategies that can be used to identify modifier genes and explain their advantages and limitations. We focus mainly on the statistical aspects but illustrate our points with a variety of examples from the literature.

Publication types

  • Review

MeSH terms

  • Genes / physiology*
  • Genetic Diseases, Inborn / genetics*
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Humans
  • Mutant Proteins / genetics*
  • Phenotype


  • Mutant Proteins