Synaptic networks shape clinical phenotypes in neurodevelopmental disorders: An integrative clinical, genetic and biological perspective

Abstract Background Clinical variability in synaptopathies suggests complex multidimensional interactions. The resulting phenotypes depend not only on the affected gene, but also on its functional role, subcellular localization, and spatiotemporal brain expression, among other potential influencing factors. Here, we present a proof of concept integrating genetic, synaptic, and developmental expression data to explore how shared pathways can lead to similar clinical manifestations across different synaptic disorders.We systematically curated published clinical data from 1,648 patients with pathogenic variants in 20 synaptic genes, through deep phenotyping using standardized Human Phenotype Ontology (HPO) annotation. Functional gene groups were defined based on synaptic localization, biological process, brain expression patterns and disease onset. Brain developmental expression data were obtained from the BrainSpan Atlas, normalized, and analyzed to assess gene co-expression and timing of peak expression. Results Integrating synaptic biology with developmental gene expression data reveals phenotypic emergence through interconnected synaptic characteristics. Subcellular localization shapes manifestations: presynaptic variants associate with motor disorders and postsynaptic variants with broader systemic involvement. Biological processes further refine phenotypes, with transport processes associated with hypotonia and signaling pathways linked to early-onset symptoms. Developmental timing adds dimension: prenatal expression peaks align with cognitive impairments and postpubertal peaks with motor decline. Crucially, clinical profiles mirror co-expression patterns of affected genes, demonstrating dynamic interactions across spatial, functional, and temporal dimensions. Conclusions By mapping symptoms into synaptic networks across developmental windows, this work establishes the foundation for a “SynGO-Clinic” platform, a clinical extension of SynGO, to advance biological insight, diagnostics, and targeted therapies in neurodevelopmental synaptopathies.