CACNA2D1 – Brugada syndrome

CACNA2D1 encodes the α2δ-1 auxiliary subunit of the L-type calcium channel critical for channel trafficking and modulation. Brugada syndrome is an autosomal dominant arrhythmia disorder characterized by ST-segment elevation and risk of sudden cardiac death, with a prevalence of approximately 1:2,000 to 1:100,000. Auxiliary subunits like α2δ-1 influence channel kinetics and may contribute to repolarization abnormalities in ventricular myocardium. The gene CACNA2D1 has been proposed as a Brugada syndrome susceptibility locus alongside established genes. However, the clinical validity of this association remains under evaluation.

In a screening of 162 unrelated Brugada syndrome and BrS+short QT probands, four distinct CACNA2D1 missense variants were reported among 16% of cases, including c.2867C>A (p.Ser956Tyr) (PMID:20817017). No familial segregation or de novo occurrences were documented, and affected relatives were not described. Follow-up analysis in the NHLBI Exome Sequencing Project (ESP) identified 272 heterozygous and 2 homozygous carriers of previously BrS-associated CACNA2D1 variants (e.g., c.2126G>A (p.Ser709Asn); c.2751A>T (p.Gln917His)), corresponding to a genotype prevalence of 1:23 in 6,258 individuals (PMID:23414114). Two of these variants (p.Ser709Asn, p.Gln917His) were also prevalent in a Danish control cohort (n=536), undermining disease specificity.

No segregation data or additional affected relatives have been reported for CACNA2D1 variants in Brugada syndrome families, limiting the genetic evidence. Functional assessment studies in murine models and cellular systems have demonstrated that α2δ-1 binds pregabalin in central nervous system regions (PMID:16460711) and that Sp1 regulates CACNA2D1 promoter activity in neuroblastoma cells (PMID:23242029). However, these data do not address cardiac electrophysiology or arrhythmogenesis directly.

Overall, conflicting evidence—case-only variant identification without segregation and high allele frequency in population controls—leads to a disputed clinical validity for CACNA2D1 in Brugada syndrome. At present, CACNA2D1 should not be used in isolation for molecular diagnosis or risk stratification of Brugada syndrome.

Key Take-home: CACNA2D1 variants lack robust genetic and functional confirmation in Brugada syndrome and are prevalent in population cohorts, disputing their pathogenic role.

References

• Heart rhythm • 2010 • Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. PMID:20817017
• Clinical genetics • 2013 • High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. PMID:23414114
• Brain research • 2006 • Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. PMID:16460711
• Pflugers Archiv : European journal of physiology • 2013 • Isolation and characterization of the 5′-upstream region of the human voltage-gated Ca(2+) channel α2δ-1 auxiliary subunit gene: promoter analysis and regulation by transcription factor Sp1. PMID:23242029

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