Linking genome variants to disease: scalable approaches to test the functional impact of human mutations

The application of genomics to medicine has accelerated the discovery of mutations underlying disease and has enhanced our knowledge of the molecular underpinnings of diverse pathologies. As the amount of human genetic material queried via sequencing has grown exponentially in recent years, so too has the number of rare variants observed. Despite progress, our ability to distinguish which rare variants have clinical significance remains limited. Over the last decade, however, powerful experimental approaches have emerged to characterize variant effects orders of magnitude faster than before. Fueled by improved DNA synthesis and sequencing and, more recently, by CRISPR/Cas9 genome editing, multiplex functional assays provide a means of generating variant effect data in wide-ranging experimental systems. Here, I review recent applications of multiplex assays that link human variants to disease phenotypes and I describe emerging strategies that will enhance their clinical utility in coming years.

Automated summary

The application of genomics in medicine has enhanced our understanding of disease mutations and molecular pathways, but determining the clinical significance of rare variants remains a challenge. Recent advances in experimental techniques have allowed for faster characterization of variant effects, providing valuable data for linking human variants to disease phenotypes.