The reversion of the mutation to wild-type may reflect a selection disadvantage to 9p24.1 cells in vitro, particularly during the process of reprogramming and neural differentiation; however, our inability to distinguish and/or purify 9p24.1 and control fibroblasts, or to repeatedly obtain skin biopsies from these two individuals, makes this a difficult hypothesis to test. We present this cautionary evidence of a heritable but unstable genetic mutation to alert hiPSC researchers to the possibility that some genetic variations may be particularly intransigent to hiPSC-based modeling at the present time. Thus, confirmation of the presence of the genetic variant in source HFs, clonal hiPSCs, and differentiated cells is essential prior to beginning phenotypic characterizations.
