The importance of rare DNA variation in neurologic disease: cautionary tale.

Abstract

Neurology has been one of the leaders in applying the developing tools of genetics to understand the etiology of disease. This extends as far back as the early 1980s, when the then-new methods of detecting DNA variation (restriction fragment length polymorphisms) were combined with relatively new analytical methods (linkage analysis) to identify the location of the Huntington disease gene,(1) Alzheimer disease genes,(2) and a Parkinson disease (PD) gene.(3) Extremely rare highly penetrant mutations in these genes are causative for disease. These discoveries redirected entire fields of study and greatly improved our understanding of the underlying pathophysiology. However, they directly explain just a tiny portion of the genetic causes of their disease.