Integrating molecular studies and clinical disease models to provide mechanistic insight into neurodevelopment: guidance from FOXG1 syndrome

Neurodevelopment relies on precise coordination across molecular, cellular, and circuit-level processes. Conventional studies into neurodevelopmental gene function are primarily guided by tissue- or cell-type-specific expression patterns and inherent protein properties or domain interactions. Consideration of human disease conditions can greatly enhance our understanding of the mechanics underlying forebrain development. In this review, we demonstrate how to combine these approaches using FOXG1 Syndrome, a rare monogenic neurodevelopmental disorder, as an example. We first summarize the core clinical features of FOXG1 Syndrome, then integrate this information with cellular and behavioral analyses of Foxg1 mutant mouse models to elucidate FOXG1's roles in distinct developmental processes, including telencephalic patterning, progenitor maintenance, neuronal migration and maturation, excitatory-inhibitory balance, and myelination. Moreover, we describe the known molecular mechanisms of FOXG1 action beyond pure transcriptional regulation. Finally, we also demonstrate how the spectrum of FOXG1 variants identified in patients, including gene-dosage changes, protein-truncating variants, missense variants, and chromosomal rearrangements, has enabled targeted functional analyses, each providing unique investigational value. Together, we aim to convey how “bedside-to-bench” directed studies can be utilized to refine classical developmental frameworks, and reveal unanticipated gene functions beyond early development.