Next-generation sequencing demands next-generation phenotyping

Abstract

Next-generation sequencing (NGS) is the most powerful diagnostic tool since the roentgenogram. NGS will facilitate diagnosis on a massive scale, allowing interrogation of all genes in a single assay. It has been suggested that NGS will decrease the need for phenotyping in general and medical geneticists in particular. We argue that NGS will shift focus and approach of phenotyping. We predict that NGS performed for diagnostic purposes will yield variants in several genes, and consequences of these variants will need to be analyzed and integrated with clinical findings to make a diagnosis. Diagnostic skills of medical specialists will shift from a pre-NGS-test differential diagnostic mode to a post-NGS-test diagnostic assessment mode. In research phenotyping and medical genetic assessments will remain essential as well. NGS can identify primary causative variants in phenotypes inherited in a Mendelian pattern, but biology is much more complex. Phenotypes are caused by the actions of several genes and epigenetic and environmental influences. Dissecting all influences necessitates ongoing and detailed phenotyping, refinement of clinical diagnostic assignments, and iterative analyses of NGS data. We conclude that there will be a critical need for phenotyping and clinical analysis, and that medical geneticists are uniquely positioned to address this need.