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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Neurodevelopmental disorders (NDD) encompass a range of conditions affecting cognitive, adaptive, motor, and speech development.
• Advances in diagnostics are identifying an increasing number of causative genes, particularly synaptic genes.
• The Calcium Calmodulin Dependent Protein Kinase type 2 (CAMK2) gene family, abundant in synapses, is a recently identified cause of NDD.

Purpose of the Study:

• To review all published cases of CAMK2-related neurodevelopmental disorders.
• To establish initial genotype-phenotype correlations for CAMK2 variants.
• To elucidate the impact of CAMK2 variants on protein function, synaptic activity, and NDD.

Main Methods:

• Systematic literature review of published CAMK2-related NDD cases.
• Analysis of genetic variations and associated clinical phenotypes.
• Correlation of genotype with observed phenotypic manifestations.

Main Results:

• A growing number of unrelated individuals with NDD carry pathogenic variations in CAMK2 genes.
• Initial genotype-phenotype correlations for CAMK2 paralogs and variant types are identified.
• Understanding of how CAMK2 variants affect synaptic function and contribute to NDD is advanced.

Conclusions:

• CAMK2 gene variations are confirmed as a cause of neurodevelopmental disorders.
• Identified genotype-phenotype correlations provide a foundation for understanding CAMK2-related symptoms.
• This review offers direction for future research into CAMK2's role in neurodevelopment and synaptic function.