Compound heterozygous variants of CACNA1H change channel properties and contribute to intractable epilepsy with myoclonic-atonic seizures.

The CACNA1H gene, which encodes the T-type calcium channel Cav3.2, is known to confer susceptibility to childhood absence epilepsy (CAE) and has been implicated in various neurological disorders. However, its pathogenic significance, especially in childhood intractable epilepsies, has not been comprehensively explored. We performed whole-exome sequencing on a 4-year-old boy diagnosed with epilepsy with myoclonic-atonic seizures (EMAtS), and identified two missense variants in CACNA1H. One was a novel variant, p.D949H, inherited from the father, while the other was a known variant, p.R788C, inherited from the mother. Because the latter was previously reported to alter Cav3.2 channel function and contribute to the pathogenesis of CAE and idiopathic generalized epilepsy, we evaluated the former's functional impact using two-electrode voltage clamp analysis in Xenopus laevis oocytes. While the current-voltage relationship of the D949H mutant channel was not significantly different from that of the wild-type channel, the time constant of recovery from inactivation was significantly prolonged in the D949H variant (671.7 ± 52.0 ms vs. 455.5 ± 28.2 ms), indicating moderately impaired properties of the mutant. Notably, neither the D949H nor the R788C variant was associated with epilepsy in either parent, suggesting that these variants were not sufficient to cause epilepsy on their own, and that the compound heterozygous state of CACNA1H contributed to the EMAtS phenotype in the proband. Our findings highlight the genetic complexity of EMAtS and underscore the importance of accumulated functional impacts of modifier variants in severe epileptic diseases, even when individual variants are not pathogenic.