From Genes to Circuits: Modeling Neurodevelopmental Disorders

<jats:p>The genetic architecture of neurodevelopmental disorders (NDDs) is increasingly well described, yet the biological meaning of many variants remains uncertain. A molecular diagnosis may identify the affected gene without explaining how the alteration perturbs brain development or why the same or related variants produce different outcomes. Variant effects are conditioned by dosage, developmental timing, cell identity and the wider genomic, epigenetic and environmental context, while compensatory responses may modify or obscure the phenotype. Functional interpretation therefore depends on linking the molecular defect to the relevant developmental and physiological consequences. This review brings together current knowledge of NDD mechanisms with the experimental and computational strategies used to test that link. No model reproduces the complete disorder, and greater complexity does not necessarily confer greater validity. The most informative system is the one that captures the biological process and developmental window relevant to the question. Concordance across models can strengthen a proposed mechanism, whereas discordant findings may reveal cellular, developmental or species-specific effects that would otherwise be missed. The same standard applies to therapeutic development: correction of a molecular abnormality is meaningful only when it produces durable functional benefit and can be achieved with appropriate central nervous system distribution, dosage and safety. Integrating functional evidence with detailed phenotyping and longitudinal clinical data may improve variant interpretation, distinguish biologically meaningful patient groups and support therapeutic strategies directed at mechanism rather than diagnostic category.</jats:p>