Abstracts

Rationale: Epilepsy is a common comorbidity in children with developmental delay and intellectual disability (DD/ID), and emerging evidence implicates voltage-gated calcium channel gene variants in its pathogenesis. This study aimed to investigate the association between epilepsy and polymorphisms in CACNA1A, CACNA1C, and CACNA1H in Korean pediatric patients with DD/ID.

Methods: Among 254 pediatric DD/ID patients who underwent whole-exome sequencing (WES), 141 without definitive monogenic diagnoses were selected, including 45 children with comorbid epilepsy. Nine functional single nucleotide polymorphisms (SNPs) across CACNA1A, CACNA1C, and CACNA1H were analyzed. Genotype and allele frequencies were compared between epilepsy and non-epilepsy subgroups, and against East Asian controls from gnomAD and the Korean Reference Genome Database (KRGDB).

Results: Patients with DD/ID and epilepsy exhibited a significantly higher frequency of language delay (82%) and a stronger family history of epilepsy (18%) compared to those without epilepsy. Among the analyzed SNPs, the CACNA1A variant rs16023 (located in the 3′ UTR) showed a significant association with epilepsy (genotype p = 0.0215). The BB genotype was observed in 11.1% of the epilepsy group but only 1.0% of the non-epilepsy group. Functional annotations supported the regulatory potential of rs16023, with a high CADD score (12.3) and a RegulomeDB score of 1f, suggesting possible effects on mRNA stability or microRNA binding.

Conclusions: Our findings suggest that the CACNA1A rs16023 variant may contribute to epilepsy susceptibility in Korean children with DD/ID. This highlights the potential role of common regulatory polymorphisms in modulating neurodevelopmental and epileptic phenotypes. Further functional validation is warranted to confirm the regulatory mechanisms underlying this association.

Funding: None.