CACNA1C Genetic Variants Differentially Affect Neuronal Networks Through Divergent Pathways

Background: dysfunction to neurodevelopmental phenotypes remain poorly understood. Methods: . Neuronal activity was assessed using multielectrode arrays, pharmacological manipulation, and gene expression analysis. Early developmental phenotypes were examined using quantitative reverse transcriptase polymerase chain reaction, immunocytochemistry, and RNA sequencing. Results: altered rosette morphology, CREB (cAMP response element binding protein) phosphorylation, and transcriptional programs related to axonogenesis and synaptic signaling, indicating effects on neuronal differentiation. The patient line exhibited opposing effects on rosette morphology and CREB signaling, reflecting variant-specific effects. Conclusions: variant effects in human neurons.