Though Rett syndrome is a monogenic disorder and should theoretically be easier to model, being an X-linked disorder introduces unique challenges due to the phenomenon of somatic X chromosome inactivation (Box 2) Nevertheless, this same phenomenon creates the unique opportunity of an isogenic control (with the same genetic background) since hiPSC lines derived from one RTT patient could either express the mutant or WT allele. Cheung et al. exploited this opportunity and derived isogenic control hiPSC lines (from RTT patient fibroblasts) expressing only the WT or the mutant MECP2 allele 92. This pattern of X-chromosome inactivation was maintained through neuronal differentiation, and similar to Marchetto et al 74, Djuric et al 86, and Ananiev et al. 80 (who also had an isogenic control), these studies found that RTT patient derived neurons with the mutant MECP2 allele had a reduced soma size compared to the isogenic controls patient derived neurons expressing WT MECP2.
