CAMK2; four genes, one syndrome? Delineation of genotype–phenotype correlations

Neurodevelopmental disorders are a heterogenous group of brain disorders impacting cognitive, adaptive, motor, and speech language development. With advancements in diagnostics an increasing number of causative genes are discovered, including synaptic genes. The calcium calmodulin dependent protein kinase type 2 (CAMK2) family is the most abundant kinase family in the synapse and has recently been established to cause NDD, with a growing number of unrelated NDD-individuals who carry pathogenic variations in one of the four CAMK2 genes. However, there is still much to learn about the specific phenotypic manifestations per CAMK2 paralog and per variant type, including the mechanism of how variants in these genes impact CAMK2 protein and synaptic functioning, and result in neurodevelopmental disorders. This review provides an overview of all CAMK2 cases published to date and reveals first genotype–phenotype correlations that can serve as a starting point to explain CAMK2 related symptoms, offering direction for future research.