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. The neuroradiologist’s role in brain malformation includes identifying likely gene culprits via pattern-recognition to guide genetic evaluation (e.g., selecting the appropriate gene panel). In the setting of an inconclusive genetic testing, the radiologist can assist by correlating variants of unknown significance with imaging features to assess pathogenicity—a process called “reverse phenotyping”. Understanding stages of brain development helps appreciate pathogenesis of brain malformation. Failure of telencephalon division in week 5, for example, will result in holoprosencephaly. Errors in corticogenesis will result in different malformation of cortical development depending on the stage of insult. Defects in axonal guidance impair development of commissural fibers (e.g., corpus callosum) and projection fibers (e.g., corticospinal tract). Finally, errors in synaptogenesis may result in epilepsy with or without a clear structural malformation on imaging. Mosaicism refers to the condition where different cells carry different genetic makeup within the same person. Its results from post-zygotic “somatic” genetic alterations. The pathogenicity of a somatic variant for brain malformation depends on 1) the type of mutational variant, 2) the type of progenitor cells affected and 3) the timing of the mutation. The MAP Kinase/mTOR pathway is linked to countless tumors and vascular malformations. It is implicated in several malformations of cortical development including focal cortical dysplasia type IIB, tuberous sclerosis and other cortical malformations in the setting of overgrowth disorders. The microtubule cytoskeleton is a dynamic structure crucial for proliferation, morphogenesis, migration, and cortical organization. Pathogenic variants in genes encoding for tubulin proteins (e.g. TUBA1A) or microtubule associated proteins (LIS or DCX) are linked with several brain malformations such as tubulinopathiesandlissencephaly, respectively. Genes encoding other forms of cytoskeletal proteins key in corticogenesis are also implicated in brain malformation. Examples include those encoding for actin cytoskeleton proteins (e.g. ACTB & ACTG1 in lissencephaly) and cytoskeletal protein filamin A (e.g. FLNA in periventricular heterotopia).