Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Childhood absence epilepsy (CAE) is a generalized epilepsy syndrome characterized by frequent brief lapses of consciousness and spike-wave discharges on electroencephalography. CACNA1H encodes the Cav3.2 T-type calcium channel, a key regulator of thalamocortical oscillations, and has been implicated as a susceptibility gene for CAE (CACNA1H; Childhood absence epilepsy).
Multiple sequencing studies in unrelated Han Chinese CAE cohorts identified 12 heterozygous missense variants in 14 of 118 probands, absent in 230 controls, supporting a role in disease susceptibility ([PMID:12891677]). No large-scale segregation data are available, and linkage analysis in European pedigrees failed to confirm a major locus. Functional assays of five patient-derived Cav3.2 mutants (including Phe161Leu) demonstrated hyperpolarizing shifts in activation and slowed inactivation kinetics, consistent with gain-of-function effects that enhance neuronal excitability ([PMID:14729682]).
Overall, CACNA1H variants have been repeatedly observed in CAE patients but show incomplete segregation and variable penetrance, suggesting a complex, oligogenic inheritance model. Electrophysiological studies provide concordant evidence that these variants perturb channel gating in directions predicted to facilitate absence seizures.
Gene–Disease AssociationModerate12 heterozygous missense variants in 14 of 118 probands absent in 230 controls; replication in independent cohorts; consistent functional data Genetic EvidenceModerateMultiple case-control studies identified CAE-specific CACNA1H variants in unrelated probands absent from controls Functional EvidenceModeratePatch-clamp studies of five variants show gain-of-function channel alterations concordant with absence seizure susceptibility |