HiPSC modeling of Fragile-X syndrome is complicated in a similar way as is modeling of Rett syndrome. Eiges et al. showed that in ESCs derived from embryos carrying the FMR1 mutation (determined through preimplantation genetic diagnosis), the FMR1 gene is expressed in ESCs but undergoes transcriptional silencing following differentiation 99. The same group later showed that FXS patient-derived hiPSCs, following reprogramming of FXS-patient-derived somatic fibroblasts, had epigenetic inactivation of the FMR1 gene 100 (Box 1). The same group also tested in their FXS hiPSC several chromatin remodeling drugs to assess the reactivation of FMR1 gene expression. To our knowledge, only two groups 101,102 created hiPSC models of FXS and studied the phenotype of FXS neurons. Both reported aberrant neuronal differentiation of these hiPSCs and showed that FXS neurons had reduced neurite outgrowth and fewer and shorter processes, echoing reports on FMR1 knockout mouse models 103,104 and post-mortem brain tissue 105101,102. Halevy et al. have also assessed and partially reversed the abnormal transcriptional signatures that may underlie the abnormalities 106. Interestingly these findings imply early neurodedevelopmental alterations, prior to synaptogenesis, although
