Much of the recent progress in treating patients with heart disease due to narrowed coronary arteries has resulted from studying disease evolution in patients with rare monogenic forms of disease. For instance, autosomal dominant familial hypercholesterolemia (FH, MIM (Mendelian Inheritance in Man) 143890) typically results from heterozygous mutations in LDLR encoding the low-density lipoprotein (LDL) receptor. Deficient LDLR activity results in elevated circulating LDL cholesterol, which accumulates within blood vessel walls, forming arterial plaques that can grow and eventually occlude the arterial lumen. Heterozygous LDLR mutations are usually detected using exon-by-exon sequence analysis (EBESA) of genomic DNA, a technology that has identified approximately 50 mutations in heterozygous FH (HeFH) subjects in Ontario. However, approximately 35% of Ontario HeFH patients had no EBESA-identified LDLR mutation. The diagnostic gap relates both to the genetic heterogeneity of FH and also to inadequate sensitivity of EBESA to detect certain mutation types, such as large deletions or insertions in LDLR. By means of a dedicated method to detect copy number variations (CNVs), additional heterozygous mutations in LDLR ranging from approximately 500 to >15 000 bases were uncovered, accounting for most of the remainder of Ontario HeFH patients. The appreciation of the key role of genomic CNVs in disease coincides with recent genome-wide mapping studies demonstrating that CNVs are common in apparently healthy people. CNVs thus represent a new level of genomic variation that is both an important mechanism of monogenic disease and a contributor to genomic variation in the general population; as well, it may have implications for evolution, biology, and possibly susceptibility to common complex diseases.