CACNA1E – Neurodevelopmental Disorder

Autosomal dominant de novo variants in CACNA1E have been implicated in neurodevelopmental disorders (MONDO:0700092), characterized by intellectual disability and often seizures. CACNA1E encodes the pore-forming α1E subunit of the R-type voltage-gated calcium channel, highly expressed in the central nervous system and critical for synaptic transmission.

In a meta-analysis of 6,753 parent–offspring trios with neurodevelopmental disorders, CACNA1E was one of 33 genes showing a significant excess of de novo variants in the subset of 1,942 individuals with epilepsy, implicating it as a novel disease gene (PMID:29942082).

Subsequent next-generation sequencing identified de novo CACNA1E variants in 30 unrelated individuals with developmental and epileptic encephalopathy (DEE) presenting with refractory infantile-onset seizures, severe hypotonia, profound developmental impairment, congenital contractures, macrocephaly, hyperkinetic movement disorders, and early mortality (PMID:30343943).

Extension of the phenotypic spectrum included seven unrelated probands with intellectual disability, developmental regression, and autism spectrum features but without seizures, each harboring de novo heterozygous CACNA1E variants (PMID:34702355).

The variant spectrum comprises 14 partially recurrent missense and nonsense substitutions clustering in the cytoplasmic ends of all four S6 segments of the channel activation gate and additional substitutions in the S4–S5 linker. A representative truncating variant is c.2485C>T (p.Arg829Ter) (PMID:30343943).

Functional assessment of several S6 segment variants revealed consistent gain-of-function effects, including facilitated voltage-dependent activation and slowed inactivation, while an S4–S5 linker variant increased current density. Pharmacological blockade of R-type calcium currents by topiramate achieved seizure freedom in five affected individuals, supporting mechanism-based therapy (PMID:30343943).

Overall, 37 independent de novo CACNA1E probands demonstrate a dominant gain-of-function mechanism leading to neuronal hyperexcitability and developmental deficits. CACNA1E should be included in diagnostic gene panels for neurodevelopmental disorders with or without epilepsy to guide precision therapy. Key Take-home: De novo CACNA1E variants cause autosomal dominant neurodevelopmental disorder via gain-of-function and respond to R-type channel inhibition.

References

• Nature genetics • 2018 • De novo variants in neurodevelopmental disorders with epilepsy. PMID:29942082
• American journal of human genetics • 2018 • De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. PMID:30343943
• Molecular autism • 2021 • De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures. PMID:34702355

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