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CACNA1G encodes the Cav3.1 T-type calcium channel, which is widely expressed in the central nervous system. Heterozygous de novo missense variants in CACNA1G have been implicated in a spectrum of neurodevelopmental disorders (MONDO:0700092), including early-onset epileptic encephalopathies, Rett-like phenotypes, and developmental delay with cerebellar involvement.
Autosomal dominant de novo inheritance is the predominant mode. Three unrelated patients in a Japanese neurodevelopmental cohort harbored previously reported ataxia alleles c.2881G>A (p.Ala961Thr) and c.4591A>G (p.Met1531Val), and one patient carried c.3817A>T (p.Ile1273Phe) (PMID:32736238). Two additional infants with developmental and epileptic encephalopathy carried c.2727G>T (p.Leu909Phe) and c.623C>G (p.Leu208Pro) (PMID:32878331). A series of 19 congenital cases, including recurrent p.Ala961Thr and p.Met1531Val and seven novel missense variants in the intracellular gate, were described in SCA42ND with neurodevelopmental deficits (PMID:39674904). No familial segregation beyond de novo occurrence has been reported.
The variant spectrum is exclusively missense, with recurrent alleles p.Ala961Thr and p.Met1531Val observed in multiple independent cases. Novel variants cluster in key functional domains: the S4 voltage sensor, pore-forming segments, and intracellular gate. Truncating, splice, or structural variants have not been described in neurodevelopmental contexts.
Functional characterization by patch-clamp in HEK293T and mammalian cells demonstrated that p.Ala961Thr and p.Met1531Val enhance T-type Ca2+ currents and low-frequency membrane oscillations (PMID:32736238). The p.Leu208Pro and p.Leu909Phe variants induce hyperpolarizing shifts in activation/inactivation and mixed gain-/loss-of-function effects (PMID:32878331). Intracellular gate mutants from the SCA42ND cohort exhibit slow inactivation/deactivation kinetics and increased window current, consistent with gain-of-function (PMID:39674904). The p.Ile1273Phe allele showed no significant biophysical alterations, leaving its pathogenicity uncertain (PMID:32736238).
Collectively, de novo gain-of-function missense variants in CACNA1G converge on a mechanism of increased thalamocortical and cerebellar excitability, explaining seizures, developmental delay, and ataxia. Experimental models are highly concordant with the clinical phenotypes, though allelic heterogeneity may modulate severity.
The weight of genetic and functional data supports a Strong ClinGen classification. CACNA1G sequencing is recommended in diagnostic panels for unexplained early-onset epilepsy and neurodevelopmental delay. The identification of gain-of-function alleles prompts exploration of T-type calcium channel modulators as targeted therapies.
Gene–Disease AssociationStrong24 probands with de novo missense variants across three independent cohorts, functional concordance Genetic EvidenceStrong24 de novo missense variants in unrelated individuals, including recurrent alleles Functional EvidenceModerateMultiple in vitro electrophysiological studies demonstrating gain-of-function for key variants |