An interaction network of genes with likely pathogenic mutations contributing to RTT in our cases. Black circles are input genes and gray circles are genes highly related to the input genes chosen by the network-building algorithm to maximize connectivity. The network was generated by using an input list of 46 genes with likely pathogenic mutations listed in as well as the 3 known RTT genes MECP2, CDKL5, and FOXG1. Of the 46 genes, 23 were found to interact amongst each other either directly or indirectly through at least one of three ways: physical interactions (orange lines), co-localization of protein products (light blue lines), and participating in the same step of a given pathway (light green lines). Asterisks indicate genes related to input genes that have been reported to either carry de novo mutations in at least one patient with other NDDs (TBL1XR1, MTMR2, AKR1C4) or whose expression has been reported to be significantly altered in a MECP2 mutant model system (DAB1, ITGA2, LAMA5), or both (GLIS2, LAMC3, SMARCE1). Network weighting was assigned based on query genes so as to maximize connectivity among input genes, and at most 20 related genes and 10 related attributes were allowed to be incorporated in the network.