Genotype-Phenotype Correlations: Assessing the Influence of Sequence Variants on the Clinical Phenotype

It used to be simple. Physicians observed patients, asked questions, examined them, and established a defined clinical phenotype. Sometimes a laboratory analyte, with a sufficient and significant correlation with the observed clinical phenotype, could be measured to provide a basis for hypothesis-driven approaches to disease pathogene-sis. Two classic examples of diseases are cystic fibrosis (CF), which is associated with increased sweat chloride concentrations, and diabetes mellitus, which is associated with increased glucose. The road to gene discovery has been considered tractable for CF because of its inheritance pattern, whereas diabetes has been considered a poly-genic disorder quite intractable to such approaches. Over the past few years, however, as mutations for a variety of disorders have been uncovered, things hav