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Background <p>To provide new insights into the pathological mechanisms of epilepsy associated with variants in the calcium channel voltage-dependent L-type alpha1C subunit gene (<i>CACNA1C</i>, NM_001129837) and to expand the phenotype of <i>CACNA1C</i>-associated neurological disorders: familial mesial temporal lobe epilepsy (FMTLE).</p> Methods <p>We conducted a comprehensive analysis of clinical data from a family affected by FMTLE and carried out genetic screening of <i>CACNA1C</i> 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.</p> Results <p>A novel <i>CACNA1C</i> variant (c.5480G &gt; 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.</p> Conclusions <p>The findings of this study provide new insights into the complex molecular mechanisms underlying <i>CACNA1C</i> variants and their correlations with patient phenotypes. This research is the first to identify <i>CACNA1C</i> as a potentially new pathogenic gene in FMTLE.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Chengzhe Wang,
  • Xintong Guo,
  • Yue Liu,
  • Dingju Long,
  • Heyu Zhang,
  • Sijing Yin,
  • Yinchao Li,
  • Yicong Liu,
  • Guanzhong Ni,
  • Ziyi Chen

摘要

Background

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).

Methods

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.

Results

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.

Conclusions

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.