Polymorphisms in CACNA1A, CACNA1C, and CACNA1H Genes in Korean Pediatric Patients with Developmental Delay and Intellectual Disability: A Focus on Epilepsy Comorbidity

Abstract

Background: Developmental delay and intellectual disability (DD/ID) are frequently accompanied by epilepsy, and growing evidence implicates variants in voltage-gated calcium channel genes in their pathogenesis. This study aimed to investigate the association of polymorphisms in CACNA1A, CACNA1C, and CACNA1H with DD/ID and epilepsy comorbidity in Korean children. Methods: We retrospectively analyzed 141 pediatric patients diagnosed with DD/ID who underwent whole-exome sequencing (WES) and were not found to have pathogenic monogenic variants. Nine single-nucleotide polymorphisms (SNPs) across CACNA1A, CACNA1C, and CACNA1H were selected based on functional annotation scores and prior literature. Genotype data were extracted from WES variant files, and allele and genotype frequencies were compared with control data from the gnomAD East Asian population and the Korean Reference Genome Database (KRGDB). Subgroup analyses were performed according to epilepsy comorbidity. Results: The CACNA1A rs16023 variant showed a significantly higher B allele frequency in DD/ID patients than in both control datasets and was also associated with epilepsy comorbidity. Genotype distribution analysis revealed that the BB genotype of rs16023 was more frequent in patients with epilepsy. Conclusions: The CACNA1A rs16023 variant may contribute to genetic susceptibility to DD/ID and epilepsy in Korean children, potentially through regulatory mechanisms. These findings support the relevance of calcium channel genes in neurodevelopmental disorders and highlight the importance of integrating functional annotation in variant prioritization.

Keywords: CACNA1A; CACNA1C; CACNA1H; developmental delay; epilepsy; intellectual disability; polymorphism.

Figure 1

Allele frequency comparison between pediatric patients with DD/ID and the general population. (a) Comparison of B allele frequencies of nine selected SNPs (rs16023, rs7249246, rs2270655, rs1006737, rs4765905, rs2007044, rs2753326, rs2753325, rs2235631) among DD/ID patients, the gnomAD East Asian population, and the Korean Reference Genome Database. The asterisk (*) indicates statistical significance (p < 0.05) in allele frequency differences. (b) Genotype distribution of rs16023 (AA, AB, BB) in patients with developmental delay/intellectual disability, stratified by epilepsy comorbidity (with vs. without epilepsy). A significant difference in genotype distribution was observed (p < 0.05).