Gene-environment (G x E) interactions significantly influence neurologic outcomes. The maternal-placental-fetal (MPF) triad, neonate, or child less than 2 years may first exhibit significant brain disorders. Neuroplasticity during the first 1000 days will more likely result in life-long effects given critical periods of development. Developmental origins and life-course principles help recognize changing neurologic phenotypes across ages. Dual diagnostic approaches are discussed using representative case scenarios to highlight time-dependent G x E interactions that contribute to neurologic sequelae. Horizontal analyses identify clinically relevant phenotypic form and function at different ages. Vertical analyses integrate the approach using systems-biology from genetic through multi-organ system interactions during each developmental age to understand etiopathogenesis. The process of ontogenetic adaptation results in immediate or delayed positive and negative outcomes specific to the developmental niche, expressed either as a healthy child or one with neurologic sequelae. Maternal immune activation, ischemic placental disease, and fetal inflammatory response represent prenatal disease pathways that contribute to fetal brain injuries. These processes involve G x E interactions within the MPF triad, phenotypically expressed as fetal brain malformations or destructive injuries within the MPF triad. A neonatal minority express encephalopathy, seizures, stroke, and encephalopathy of prematurity as a continuum of trimester-specific G x E interactions. This group may later present with childhood sequelae. A healthy neonatal majority present at older ages with sequelae such as developmental disorders, epilepsy, mental health diseases, tumors, and neurodegenerative disease, often during the first 1000 days. Effective preventive, rescue, and reparative neuroprotective strategies require consideration of G x E interactions interplay over time. Addressing maternal and pediatric health disparities will maximize medical equity with positive global outcomes that reduce the burden of neurologic diseases across the lifespan.
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