The prognosis of epilepsy patients with CACNA1H missense variants: A longitudinal cohort study

CACNA1H is regarded as a gene conferring susceptibility to generalised epilepsy. However, the prognosis of epilepsy patients carrying the CACNA1H missense variants of uncertain significance (VUS) is unknown. A prospective cohort was generated to determine the deleterious effects of these variants and to check whether the presence of these variants affects the prognosis of epilepsy patients.

This study was conducted at Xijing Hospital in Xian, China. All patients were followed up for at least 1 year. Previous reports were searched for previously reported variants. Ensembl database was searched for variants in the general population. Combined Annotation Dependent Depletion (CADD) was used to evaluate the deleterious effect of variants. Logistic regression and Cox regression were used for data analysis.

The study included 176 epilepsy patients with or without CACNA1H variants. In epilepsy patients with missense variants, we found 35 different variants, including 33 variants with uncertain significance and 2 likely benign variants. No significant difference was observed between the distribution of CADD scores of the variants from this cohort, of the general population, and of those found in previous reports. Among epilepsy patients with missense variants, the number of antiepileptic drugs (AEDs) administered to the patients, a first-degree family history of epilepsy, and possibly the presence of abnormalities in brain radiology findings were correlated with the poorer prognosis. Among the entire cohort, the type of epilepsy, number of AEDs administered, and presence of abnormalities in brain radiology findings were associated with the prognosis of these patients. The deleterious effect of CACNA1H missense variants or their presence was not related to the prognosis of epilepsy patients.

The results of our study suggest that CACNA1H variants are related to multiple epilepsy syndromes. However, there is no strong evidence of the correlation between CACNA1H missense variants and a certain type of epilepsy. In our study cohort, both the deleterious effects and the presence of CACNA1H variants were found to be unrelated to the prognosis of patients with epilepsy. These findings suggest that CACNA1H missense variants that are classified as VUS might not influence the outcome of epilepsy.