Characterizing developmental and behavioral profiles in developmental synaptopathies to inform clinical trial endpoints

Background: The Developmental Synaptopathies Consortium is a multi-site natural history network studying rare, neurogenetic syndromes associated with synaptic dysfunction and developmental delays. One aim of the Consortium is clinical trial readiness, including identifying clinical concepts and validating their measurement. Methods: We evaluated the scope and limitations of conventional cognitive and behavioral measurement strategies in 2–21-year-olds with Phelan-McDermid syndrome (PMS, N=98), Tuberous Sclerosis Complex (TSC, N=98) and PTEN Hamartoma Tumor syndrome (PHTS, N=69). Results: On average, intellectual disability (ID) severity was severe-to-profound in PMS, mild-to-moderate for TSC, and borderline (or absent) in PHTS. Severity of ID invalidated the use of many assessments, including standardized autism diagnostic measures. Conclusions: These results will inform trial planning for these and other similarly medically complex neurodevelopmental conditions.