Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition whose pathophysiology is thought to arise from complex interactions among genetic variation, molecular and cellular perturbations, and neural circuit dysfunction. Although the distinction between syndromic and non-syndromic ASD was introduced as a pragmatic clinical classification, these clinically defined subgroups may exhibit overlapping yet distinct patterns of genetic liability and molecular dysregulation while also exhibiting mechanistic convergence. This narrative review examines the molecular mechanisms underlying synaptic development, structure, and function, with particular emphasis on the roles of chromatin remodeling and epigenetic regulation in neurodevelopment. It further considers how molecular and cellular alterations may contribute to impaired functional integration at the neural circuit level. By comparing the shared and unique genes and pathways associated with syndromic and non-syndromic ASD, the review identifies potential points of mechanistic convergence across multiple levels of biological organization. To integrate these findings, the review proposes a three-layer hierarchical framework that links gene function (Layer 1), core biological pathways (Layer 2), and clinical phenotypes (Layer 3). By mapping ASD-associated genes onto a functional continuum ranging from local synaptic effectors to global regulators of chromatin and gene expression, this framework illustrates how subtype-enriched genetic factors may give rise to both shared and unique molecular, cellular, and circuit-level alterations. The proposed framework may help identify common and subtype-enriched biological mechanisms, inform biomarker discovery, and provide a conceptual basis for mechanism-informed ASD research and biologically grounded clinical stratification.