Expanding clinical phenotype in CACNA1C related disorders: familial mesial temporal lobe epilepsy

TL;DR

This study identifies a new CACNA1C gene variant linked to a milder form of familial mesial temporal lobe epilepsy, expanding the known clinical features of this disorder.

Contribution

The study reports a novel CACNA1C variant and expands the clinical phenotype of CACNA1C-related disorders.

Findings

A novel CACNA1C variant (c.5480G > A, p.R1827Q) was identified in a family with FMTLE.

The variant is associated with a milder clinical phenotype compared to previous reports.

Bioinformatics and molecular dynamics simulations suggest the variant causes structural changes in the protein.

Abstract

To provide new insights into the pathological mechanisms of epilepsy associated with variants in the calcium channel voltage-dependent L-type alpha1C subunit gene (CACNA1C, NM_001129837) and to expand the phenotype of CACNA1C-associated neurological disorders: familial mesial temporal lobe epilepsy (FMTLE).

We conducted a comprehensive analysis of clinical data from a family affected by FMTLE and carried out genetic screening of CACNA1C variants through whole-exome sequencing combined with Sanger sequencing for validation. The clinical characteristics of FMTLE were systematically reviewed, and the pathogenic potential of the identified variant was assessed following the guidelines established by the American College of Medical Genetics and Genomics (ACMG). To explore the underlying pathogenic mechanisms, we utilized bioinformatics tools alongside molecular dynamics simulation methods.

A novel CACNA1C variant (c.5480G > A, p.R1827Q) was identified in a large family with FMTLE. Unlike previous reports, the clinical phenotype of this genotype differs from previous reports, being mild, with focal to bilateral tonic–clonic seizures being more common. Bioinformatics analysis and molecular dynamics simulations indicated that this variant induces local structural changes in the protein.

The findings of this study provide new insights into the complex molecular mechanisms underlying CACNA1C variants and their correlations with patient phenotypes. This research is the first to identify CACNA1C as a potentially new pathogenic gene in FMTLE.

The online version contains supplementary material available at 10.1186/s42494-025-00231-5.

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