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CACNA2D1 encodes the α2δ-1 auxiliary subunit of voltage-gated calcium channels. Autosomal recessive loss-of-function variants in CACNA2D1 have been identified in two unrelated individuals presenting with early-onset developmental delay and refractory seizures ([PMID:35293990]). Patient 1 is homozygous for c.818_821dup (p.Ser275AsnfsTer13), resulting in nonsense-mediated mRNA decay. Patient 2 is compound heterozygous for c.13_23dup (p.Leu9AlafsTer5) and c.626G>A (p.Gly209Asp), with all alleles segregating with disease in each family ([PMID:35293990]).
Functional studies in patient-derived fibroblasts show complete absence of α2δ-1 protein, while heterologous expression of p.Gly209Asp reveals severely reduced cell-surface trafficking and failure to enhance CaV2 channel currents, confirming a loss-of-function mechanism ([PMID:35293990]). Together, these data support a limited ClinGen gene–disease association for CACNA2D1 and developmental and epileptic encephalopathy. Sequencing of CACNA2D1 should be considered in diagnostic panels for early-onset epileptic encephalopathies.
Gene–Disease AssociationLimitedTwo unrelated probands with biallelic CACNA2D1 loss-of-function variants and supportive functional data ([PMID:35293990]) Genetic EvidenceLimitedBiallelic frameshift and missense variants in two unrelated individuals with consistent phenotype ([PMID:35293990]) Functional EvidenceModeratePatient fibroblast studies showing absence of α2δ-1 protein and heterologous assays demonstrating trafficking and functional impairment of p.Gly209Asp variant ([PMID:35293990]) |