CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications

Xue-Lian Li; Zong-Jun Li; Xiao-Yu Liang; De-Tian Liu; Mi Jiang; Liang-Di Gao; Huan Li; Xue-Qing Tang; Yi-Wu Shi; Bing-Mei Li; Na He; Bin Li; Wen-Jun Bian; Yong-Hong Yi; Chuan-Fang Cheng; Jie Wang

doi:10.3389/fnmol.2022.860662

CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications

Front Mol Neurosci. 2022 May 4:15:860662. doi: 10.3389/fnmol.2022.860662. eCollection 2022.

Authors

Xue-Lian Li^{1

2}, Zong-Jun Li¹, Xiao-Yu Liang¹, De-Tian Liu¹, Mi Jiang¹, Liang-Di Gao¹, Huan Li¹, Xue-Qing Tang¹, Yi-Wu Shi¹, Bing-Mei Li¹, Na He¹, Bin Li¹, Wen-Jun Bian¹, Yong-Hong Yi¹, Chuan-Fang Cheng^{1

3}, Jie Wang¹

Affiliations

¹ Key Laboratory of Neurogenetics and Channelopathies of the Ministry of Education of China, Department of Neurology, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
² Department of Neurology, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, China.
³ Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.

Abstract

Purpose: Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity.

Methods: Trio-based whole-exome sequencing was performed in 318 cases with partial epilepsy and 150 cases with generalized epilepsy. We then reviewed all previously reported CACNA1A mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications.

Results: We identified 12 CACNA1A mutations in ten unrelated cases of epilepsy, including four de novo null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G > A, c.4755 + 1G > T, and c.6340-1G > A), four de novo missense mutations (c.203G > T/p.Arg68Leu, c.3965G > A/p.Gly1322Glu, c.5032C > T/p.Arg1678Cys, and c.5393C > T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu and c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys). The eight de novo mutations were evaluated as pathogenic or likely pathogenic mutations according to the criteria of American College of Medical Genetics and Genomics (ACMG). The frequencies of the compound heterozygous CACNA1A mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (P = 7.30 × 10^-4, P = 2.53 × 10^-4). All of the ten cases were ultimately seizure-free after antiepileptic treatment, although frequent epileptic seizures were observed in four cases. Further analysis revealed that episodic ataxia type 2 (EA2) had a tendency of higher frequency of null mutations than epilepsies. The missense mutations in severe epileptic phenotypes were more frequently located in the pore region than those in milder epileptic phenotypes (P = 1.67 × 10^-4); de novo mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (P = 1.92 × 10^-3).

Conclusion: This study suggested that CACNA1A mutations were potentially associated with pure epilepsy and the spectrum of epileptic phenotypes potentially ranged from the mild form of epilepsies such as absence epilepsy or partial epilepsy, to the severe form of developmental epileptic encephalopathy. The clinical phenotypes variability is potentially associated with the molecular sub-regional of the mutations.

Keywords: CACNA1A; childhood absence epilepsy; genotype-phenotype correlation; molecular sub-regional implication; partial epilepsy.