Susceptibility genes and modifier genes are two biologic phenomena that few clinicians should ignore in the genome era. Susceptibility genes, which are genes with functional variants that affect the causes of disease, are routinely being identified for simple mendelian diseases and, more recently, for common genetic disorders. Modifier genes are distinct from susceptibility genes, in that they are genetic variants that affect the clinical manifestation of disease (as opposed to liability). However, the identification of modifier genes has proven elusive.

Since the discovery of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989,¹ considerable efforts . . .