Opposing excitatory and inhibitory synaptic pathologies drive ZC4H2-associated intellectual disability

Understanding genotype-phenotype correlations is critical for precision medicine, yet patients carrying mutations in the same gene are often classified under one disorder and treated alike, despite potentially opposite responses to therapy. ZC4H2-associated rare disorder (ZARD) is an X-linked neurodevelopmental condition caused by diverse mutations across ZC4H2. Here, we show that distinct ZC4H2 mutations drive intellectual disability through opposing synaptic mechanisms. The gain-of-function mutation ZC4H2^L66H enhances GABA_A receptor (GABA_AR) degradation, impairing inhibitory synaptic transmission and plasticity. By contrast, the loss-of-function mutation ZC4H2^R213W increases AMPA receptor (AMPAR) stability and dysregulates excitatory synaptic activity. Despite these diametrically opposed synaptic pathologies, ZC4H2^L66H/y and ZC4H2^R213W/y knockin mice exhibit comparable cognitive deficits. Importantly, muscimol, a GABA_AR agonist, specifically rescues deficits in ZC4H2^L66H/y mice, whereas the AMPAR antagonist perampanel rescues ZC4H2^R213W/y mice. These findings demonstrate that opposing synaptic etiologies can underlie a single genetic disorder and highlight pathomechanism-based stratification for targeted therapeutic strategies.