These are not restricted to conditions such as Cystic Fibrosis and Muscular Dystrophy that are solely due to rare, high penetrance Mendelian mutations. There are numerous chronic conditions that have familial analogs: well-known examples include rare variants promoting atherosclerosis through hypercholesterolemia39, the lesions responsible for Maturity Onset Diabetes of the Young (MODY)40, and the BRCA1 and BRCA2 breast cancer susceptibility mutations41. In fact, perusal of the Online Mendelian Inheritance in Man (OMIM) database provides examples of near-Mendelian cases of many relatively common disorders42. Probably the most comprehensive survey of this model is the demonstration that half of the cases of X-linked mental retardation can be ascribed to rare protein-coding mutations, which were discovered by comprehensive sequencing of X-chromosomal exons43. There is thus extensive precedent for rare variants contributing substantially to special cases of complex disease, including risk of infection44.
