Schizophrenia (SCZ) is a highly heritable psychiatric disorder with disabling psychotic and cognitive symptoms and existing treatments are only partially effective in restoring function. Given the extensive elimination of synapses by microglia in the human cerebral cortex during early development, it has been proposed that excessive synaptic pruning may contribute to the observed reduction in gray matter thickness and synapse density in SCZ patients. We modelled synaptic pruning using patient-derived stem-cell-based forebrain organoids, containing innately developed microglia, and assessed microglia-mediated synaptic engulfment across three monozygotic twin pairs (MZ) discordant for SCZ. 3D cellular reconstructions revealed a significant increase in the uptake of synaptic material by microglia in SCZ-affected individuals, thus, highlighting the complicity of synaptic pruning in driving the pathophysiology of SCZ during early brain development. Paired single-cell multi-omic (RNA and ATAC) sequencing revealed vast transcriptional and chromatin differences across major cell types during neurodevelopment in MZ twins discordant for SCZ, including microglia. We hypothesized that early post-twinning mutational events in the genome could lead to such phenotypic discordances and confirmed a fraction of de novo structural events (n=21), discordant within individual twin pairs in genotype arrays. We further mapped transcriptional and chromatin activity at regions harboring de novo variants to understand regulatory mechanisms underlying the phenotypic differences amongst respective twin pairs. Deciphering the functional consequences of such de no events in MZ twins discordant for psychiatric disorders such as schizophrenia holds promising potential in identifying unique causal candidates otherwise undetected in genomic association studies of psychiatric disorders.