Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap.
Keywords: GWAS; bioinformatics; expressivity; genetic interaction; genetic modifier; genome sequencing; mendelian disease; penetrance; phenotypic variability; rare disease.