Disease-modifying genes and monogenic disorders: experience in cystic fibrosis

Abstract

The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.

Keywords: candidate gene approach; cystic fibrosis; genome wide association studies; genotype; modifier genes; phenotype.

Figure 1

Scheme of the relationship between genotype and phenotype, and the influence of additional factors such as modifier genes, entire genetic background, epigenetic, and environmental effects on cystic fibrosis. Notes: In primarily monogenic disorders, the phenotype is significantly defined by the disease-causing mutations while direct and indirect modifier genes followed by the entire genetic background, epigenetics, and environment essentially induce phenotypic variability. Multifactorial and complex diseases, however, are mostly the result of one or several genetic predispositions triggered by exogenous factors. Yellow circles represent modifiers enhancing CFTR disease severity, and blue circles represent modifiers with a protective effect against CFTR. The beige circles represent the genetic background, and the red shapes show the methylation of specific genes (epigenetic influences). Direct modifiers are shown without an arrowhead, and indirect modifiers with an arrowhead. A range of environment effects (eg, chemicals, climate, drugs, infections, radiation) are shown in the outer circle. Abbreviation: CFTR, cystic fibrosis transmembrane conductance regulator.