Identification of CDK5RAP2 as a causative gene of focal epilepsy without microcephaly.

Objective: The CDK5RAP2 gene, which encodes a regulator of cyclin-dependent kinase activity, plays a vital role in brain development. CDK5RAP2 variants have been previously reported in patients with primary microcephaly-3, with or without epilepsy. This study aimed to investigate the association between CDK5RAP2 and epilepsy.

Method: Trio-based whole-exome sequencing was performed in patients with idiopathic focal epilepsy without acquired causes. Sub-regional effects, genotype-phenotype correlation, and protein-protein interactions were analysed to reveal gene-disease association.

Results: Four compound heterozygous CDK5RAP2 variants were identified in four unrelated cases. These variants had no or extremely low allele frequencies in the controls and showed statistically higher frequencies than those in the controls. These variants were predicted to have changes in hydrogen bonds, decreased protein stability, and significant alterations in the hydrophobicity. All patients had focal epilepsy without microcephaly. Patient in one case with two variants of paired missense variants located at the functional domain showed refractory seizures, whereas another patient with variants outside functional domains was seizure-free, suggesting a potential sub-regional effect. The proportion of missense variants in the epilepsy group was significantly higher than that in the primary microcephaly group, suggesting a potential genotype-phenotype correlation. Protein-protein interaction analysis showed that CDK5RAP2 interacted with 31 proteins with high confidence, of which 13 genes were associated with epilepsy and neurodevelopmental disorders, suggesting a potential association between CDK5RAP2 and epilepsy.

Conclusion: CDK5RAP2 is a novel causative gene for focal epilepsy without microcephaly.