Perinatal insults, genetic susceptibility, and the pathogenesis of neurodevelopmental disorders: from epigenetic remodeling to neural circuit dysfunction—a narrative review

Abstract

Background and Objective Neurodevelopmental disorders (NDDs)—including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability (ID), epilepsy, and schizophrenia—affect approximately 10–15% of children worldwide. Emerging evidence suggests that NDDs arise from complex interactions between genetic susceptibility and environmental insults, particularly during perinatal periods. This narrative review aims to synthesize current evidence on the molecular and circuit-level mechanisms linking perinatal insults and genetic vulnerabilities to NDD pathogenesis, and to propose an integrative framework across epidemiology, genetics, epigenetics, and neurobiology. Methods We searched PubMed/MEDLINE, Web of Science, and Google Scholar for articles published from January 2000 to April 2026, combining terms for NDDs, genetic susceptibility, perinatal exposures, and molecular mechanisms. We prioritized original research, meta-analyses, systematic reviews, and consortium studies; human studies were given precedence, with animal and organoid studies included only when providing unique mechanistic insights. Key Content and Findings The review covers five themes: (I) genetic architecture from rare variants to polygenic risk; (II) gene-environment interplay, distinguishing true interaction from genetic confounding; (III) epigenetic mediation (DNA methylation, histone modifications, noncoding RNAs); (IV) circuit dysfunction from synaptic/ion channel deficits to brain-wide networks (cortex, cerebellum, thalamus, brainstem); and (V) emerging therapeutic strategies with a translational roadmap. Its distinctive innovation lies in integrating these layers across developmental time, proposing epigenetic remodeling as a key molecular transducer linking early insults to persistent circuit dysfunction. Conclusions Critical gaps persist—ancestry bias, lack of unified quantitative risk models, and limited therapy translation. Future priorities include diversifying genomic cohorts, establishing multi-omic birth cohorts, developing early-detection biomarkers for the perinatal window, and evaluating targeted interventions in genetically defined subgroups. This integrative framework aims to guide developmentally sensitive, precision-oriented approaches to NDD research and clinical care.