CACNB4 – Epilepsy

CACNB4 encodes the auxiliary β4 subunit of voltage-gated calcium channels, critical for presynaptic CaV2.1 complex assembly and nuclear signaling. Heterozygous loss-of-function and missense alleles in CACNB4 have been implicated in various epilepsy phenotypes, linking disrupted channel kinetics to seizure susceptibility. The disease–gene link is supported by both case series and experimental concordance.

Genetic Evidence

Autosomal dominant inheritance is suggested by de novo and familial heterozygous variants. In a cohort of 25 sporadic epilepsy cases, three unrelated patients harbored a one-base insertion c.78_79insG (p.Asp27GlyfsTer26) leading to a frameshift and premature truncation ([PMID:35813387]). A premature-termination variant c.1444C>T (p.Arg482Ter) was identified in a juvenile myoclonic epilepsy pedigree, and a missense c.311G>T (p.Cys104Phe) segregated in two families with generalized epilepsy ([PMID:10762541]).

Segregation analysis demonstrated co-segregation of c.311G>T in two affected relatives, supporting pathogenicity. In total, 6 probands across 3 sporadic and 2 familial cases have been reported.

Functional Evidence

Functional assays in Xenopus oocytes of R482X (p.Arg482Ter) demonstrated altered inactivation kinetics of the α1 subunit, consistent with gain-of-function effects on channel kinetics ([PMID:10762541]). Heterologous expression of the homozygous missense p.Leu126Pro variant (modeled in rat β4b) abolished stable association with α1 complexes, prevented presynaptic clustering and nuclear targeting in neuronal cultures, and impaired channel modulation ([PMID:32176688]).

Integrated Conclusion

The convergence of multiple unrelated probands carrying truncating and missense CACNB4 variants, segregation in familial cases, and complementary functional data supports a Strong clinical validity classification for CACNB4 in epilepsy. Further large-scale screening will refine prevalence and spectrum.

Key Take-home: Heterozygous CACNB4 variants disrupting calcium channel assembly and regulation underlie a dominantly inherited form of epilepsy, with implications for genetic testing and targeted therapies.

References

• Frontiers in pediatrics • 2022 • Whole-Exome Sequencing Identifies Novel SCN1A and CACNB4 Genes Mutations in the Cohort of Saudi Patients With Epilepsy. PMID:35813387
• American journal of human genetics • 2000 • Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. PMID:10762541
• PLoS genetics • 2020 • A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions. PMID:32176688

Evidence Based Scoring (AI generated)