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Epilepsy, Developmental Disorders Linked to De Novo Mutations in Calcium Channel Subunit

NEW YORK (GenomeWeb) – An international team led by researchers at the University of Washington, the University of Tubingen, and Children's Hospital of Philadelphia has identified de novo mutations in the calcium voltage-gated channel subunit gene CACNA1E that contribute to epilepsy and developmental disorders in childhood.

For a study published in the American Journal of Human Genetics, the researchers searched for suspicious genetic variants in 30 individuals with neurodevelopmental conditions called "developmental and epileptic encephalopathies" (DEEs) that are marked by seizures, epilepsy-like brain activity, and developmental impairment or regression. Using exome and/or whole-genome sequence data for the affected children and their parents, they narrowed in on 14 de novo pathogenic CACNA1E mutations, most often in a portion of the gene coding for a calcium channel activation gate.

"All identified individuals with CACNA1E encephalopathy present with similar clinical features, including profound developmental impairment, infantile-onset refractory epilepsy, and severe axial hypotonia," corresponding and co-senior author Heather Mefford, a genetic medicine researcher at the University of Washington, and her colleagues wrote.

The team's follow up calcium channel, site-directed mutagenesis, and cell line experiments indicated that these variants led to gain-of-function activity following voltage activation and slower-than-usual inactivation. Treatment with an R-type calcium channel blocking anti-epileptic drug called topiramate led to better seizure control over the short or long term in five of the affected children, the group reported, including two patients who did not have seizures for years after the treatment.

"We implicate facilitated R-type calcium currents as a disease mechanism in human epilepsy, which provides a promising target for the development of precision medicines for this devastating disease," the authors wrote.

The team's analyses included diagnostic exome trio sequencing data generated at GeneDx, Ambry Genetics, and ARUP Laboratories, along with parent-child trio exomes sequenced on a research basis. The group noted that whole-genome sequencing and confirmatory Sanger sequencing was used to assess three affected individuals and their parents.

After identifying missense CACNA1E variants in 30 patients, the researchers tracked down three more cases with milder clinical phenotypes that involved mutations suspected to cause CACNA1E haploinsufficiency.

Although the functional consequences of haploinsufficiency-causing mutations in the gene have yet to be investigated further, their own functional analyses of missense mutations in the gene, together with prior studies, implicated specific CACNA1E variants in calcium channel voltage activation.

"Functional analysis revealed dramatic gain-of-function effects, indicating increased calcium inward currents that may affect neuronal excitability and synaptic transmission," the authors wrote. "The identification of pathogenic gain-of-function variants in CACNA1E in these individuals adds to the growing list of channelopathies causing neurodevelopmental disorders and DEEs."