Radiogenomics of congenital brain malformations: Linking embryology, genetics, and imaging

Congenital brain malformations are structural anomalies present at birth stemming from underlying genetic mutations or prenatal disruptions. The increased use of advanced genomic sequencing has led to major breakthroughs in pediatric neurogenetics; however, progress in unraveling the genetic basis of many central nervous system (CNS) malformations has lagged. This gap is partly due to the complexity of brain development and challenges like establishing the genetic culprit in somatic mosaicism. This review aims to integrate embryology, genetics, and neuroimaging to provide a practical radiogenomic framework for congenital brain malformations.

A narrative review of the literature was performed focusing on fundamental embryologic processes of CNS development, genetic concepts relevant to malformations, and key molecular pathways and protein structures implicated in neurodevelopment. Representative malformations of cortical development, midline anomalies, and hindbrain malformations are discussed with emphasis on radiologic-genetic correlations.

Critical developmental pathways and proteins-including mTOR and Ras/MAPK signaling cascades and the tubulin cytoskeleton-are central to the pathogenesis of congenital brain malformations. Genetic principles, such as types of genetic alterations (e.g. somatic vs germline), mosaicism, penetrance, and expressivity explain the imaging and clinical phenotype variability and the diagnostic challenges encountered. Distinct radiogenomic patterns are identified across malformations of cortical development, corpus callosum anomalies, holoprosencephaly and posterior fossa malformations highlighting the diagnostic value of integrating neuroimaging with embryologic and molecular insights.

Radiogenomic correlation of congenital brain malformations is increasingly important in the era of precision medicine. By correlating neuroimaging phenotypes with the relevant embryologic and molecular mechanism, neuroradiologists can improve diagnostic accuracy, guide genetic testing strategies, and contribute to multidisciplinary care and counseling.