HiPSCs have proved quite helpful in further validating findings from previous pathological and rodent model studies of monogenic disorders, especially when coupled with a comparison between isogenic lines. Since most of the variation between hiPSC lines is due to genetic background effects 35, comparison between isogenic lines when investigating the phenotypic effect of single genes can be quite powerful. Yet, isogenic pairs do not completely resolve the issue of modeling disorders. One reason for this is that even in the so-called monogenic disorders, penetrance can vary substantially depending upon the genetic background. This requires the investigation of single genes’s mutations in multiple genetic backgrounds.
