Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy

Summary Objective Genetic generalized epilepsy ( GGE ) encompasses seizure disorders characterized by spike‐and‐wave discharges ( SWD ) originating within thalamo‐cortical circuits. Hyperpolarization‐activated ( HCN ) and T‐type Ca 2+ channels are key modulators of rhythmic activity in these brain regions. Here, we screened HCN 4 and CACNA 1H genes for potentially contributory variants and provide their functional analysis. Methods Targeted gene sequencing was performed in 20 unrelated familial cases with different subtypes of GGE , and the results confirmed in 230 ethnically matching controls. Selected variants in CACNA 1H and HCN 4 were functionally assessed in tsA201 cells and Xenopus laevis oocytes, respectively. Results We discovered a novel CACNA 1H (p.G1158S) variant in two affected members of a single family. One of them also carried an HCN 4 (p.P1117L) variant inherited from the unaffected mother. In a separate family, an HCN 4 variant (p.E153G) was identified in one of several affected members. Voltage‐clamp analysis of CACNA 1H (p.G1158S) revealed a small but significant gain‐of‐function, including increased current density and a depolarizing shift of steady‐state inactivation. HCN 4 p.P1117L and p.G153E both caused a hyperpolarizing shift in activation and reduced current amplitudes, resulting in a loss‐of‐function. Significance Our results are consistent with a model suggesting cumulative contributions of subtle functional variations in ion channels to seizure susceptibility and GGE .