Modifiying genes in hereditary diseases

Many hereditary diseases are phenotypically variable. The phenotype can be more or less severe between families and within families. Three main factor s can cause this phenotypic variability: allelic and non allelic heterogene ity, modifiying genes, environmental differences. Modifiying genes which, w hile not causing the disease may be related to its severity. The modifiying genes can concern a qualitative feature of the disease, i.e. different sub sets of organs can be affected, or a quantitative one, a different age of o nset can be noted. Three groups of modifier genes can be considered: (1) Al lelic or heteroallelic variants of the deleterious gene. (2) Genes very clo sely linked to the deleterious allele (chromosomal background). (3) non all elic genes. Strategies for the identification of modifiying genes are simil ar to those used in genetic epidemiology. Two methods are used, association studies and affected sibling pairs analysis. In both cases the candidate g ene approache is privileged. Understanding the pathogenesis of a disease an d/or animal models may provide clues to likely candidate genes.