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

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

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=15

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.860662

DOI=10.3389/fnmol.2022.860662

ISSN=1662-5099

ABSTRACT=<sec><title>Purpose</title><p>Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (<italic>CACNA1A</italic>) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between <italic>CACNA1A</italic> and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity.</p></sec><sec><title>Methods</title><p>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 <italic>CACNA1A</italic> mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications.</p></sec><sec><title>Results</title><p>We identified 12 <italic>CACNA1A</italic> mutations in ten unrelated cases of epilepsy, including four <italic>de novo</italic> null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G &gt; A, c.4755 + 1G &gt; T, and c.6340-1G &gt; A), four <italic>de novo</italic> missense mutations (c.203G &gt; T/p.Arg68Leu, c.3965G &gt; A/p.Gly1322Glu, c.5032C &gt; T/p.Arg1678Cys, and c.5393C &gt; T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A &gt; G/p.Ile1631Val&amp; c.5978C &gt; T/p.Pro1993Leu and c.3233C &gt; T/p.Ser1078Leu&amp;c.6061G &gt; A/p.Glu2021Lys). The eight <italic>de novo</italic> 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 <italic>CACNA1A</italic> mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (<italic>P</italic> = 7.30 × 10<sup>–4</sup>, <italic>P</italic> = 2.53 × 10<sup>–4</sup>). 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 (<italic>P</italic> = 1.67 × 10<sup>–4</sup>); <italic>de novo</italic> mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (<italic>P</italic> = 1.92 × 10<sup>–3</sup>).</p></sec><sec><title>Conclusion</title><p>This study suggested that <italic>CACNA1A</italic> 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.</p></sec>