A Proposed Extracellular Matrix–Synaptic Axis Connecting Hypermobile Ehlers-Danlos Syndrome and Autism Spectrum Disorder: An In Silico Network Analysis

Hypermobile Ehlers-Danlos syndrome (hEDS) and autism spectrum disorder (ASD) arefrequently reported as comorbid conditions, yet the biological mechanisms underlyingthis association remain poorly understood. Recent evidence suggests that extracellularmatrix (ECM) dysregulation, altered matrix remodeling, integrin signaling, and cellularstress pathways may contribute to hEDS pathophysiology, while synaptic dysfunction,mTOR signaling abnormalities, and impaired neurodevelopmental processes are centralfeatures of ASD. In this study, we explored a proposed ECM–synaptic axis linking hEDS and ASDthrough a literature-derived molecular interaction network. A network containing 22genes and 23 experimentally supported interactions was constructed using NetworkX.Topological analyses, community detection, and in silico knockout simulations wereperformed to identify central nodes and functional modules. Network analysis revealed a structured organization composed of six molecularcommunities connecting ECM components, perineuronal network molecules, integrinsignaling proteins, mTOR/autophagy regulators, and ASD-associated synaptic genes.TNXB emerged as the most influential node, displaying the highest degree andbetweenness centrality and producing the greatest network fragmentation followingsimulated removal. RELN, HAPLN1, and SHANK3 also showed high bridgingproperties, suggesting important roles in connecting extracellular matrix andneurodevelopmental pathways. Community analysis identified biologically coherentmodules enriched for ECM/perineuronal network functions, synaptic genes, integrinmTOR signaling, matrix remodeling, and autophagy-related processes. These findings support the plausibility of an ECM-centered molecular framework linkingconnective tissue biology and neurodevelopmental dysfunction. Although exploratoryand hypothesis-generating in nature, the proposed network highlights TNXB, RELN,and HAPLN1 as potential molecular bridges between hEDS and ASD and providesexperimentally testable predictions for future transcriptomic, proteomic, and functionalstudies.