By James T. Lu, Philippe M. Campeau, and Brendan H. Lee
New England Journal of Medicine
August 14, 2014
Ever since Mendel observed the varied phenotypes of peas — green or yellow, smooth or wrinkled — phenotypes have been used to systematically identify the genetic causes of disease. Similarly, genotype–phenotype relationships in humans could be dissected only if there were clearly recognizable, and relatively homogeneous, phenotypes. Since broad searches of genetic information were not technically feasible or cost-effective before the advent of next-generation sequencing (NGS), scientists studied well-characterized families to narrow the list of plausible genetic causes. However, being restricted to this set of “solvable” genetic problems led to ascertainment biases that favored highly penetrant mutations with straightforward functional consequences — that is, loss of function, gain of function, or dominant negative mutations dramatically affecting protein function. Thus, genetic studies before NGS systematically underestimated the true amount of genetic variation.
