Our results indicate that the existence of de novo variants in genes with potential neurological functionalities, such as neuronal receptors (GABBR2 and CHRNA5), axon guiders (SEMA6B), synaptic ionic channels (CACNA1I) and others, contribute to the development of RTT-like clinical phenotypes in the context of wild-type sequences for standard Rett genes such as MECP2 and FOXG1. These patients share most of the clinicopathological features of classic RTT syndrome, such as stereotypic hand movements, relative microcephaly, and onset of the disease after the age of 12 months. The gene discussed is SEMA6B; the disease is Rett syndrome.