CACNB2 – Short QT Syndrome

Short QT syndrome is a rare inheritable arrhythmogenic disorder characterized by abbreviated ventricular repolarization and a high risk of syncope and sudden cardiac death. CACNB2 encodes the β2-subunit of the L-type calcium channel and has been implicated in SQTS subtype 5. The gene–disease association has been evaluated in multiple families with corroborating functional data. Understanding CACNB2’s role in SQTS supports diagnostic stratification and targeted management.

Genetic screening of 17 patients from seven independent families demonstrated that 76% harbored pathogenic variants in SQTS genes, including six individuals with CACNB2 mutations ([PMID:30571592]). These cases exhibited an autosomal dominant inheritance pattern with a family history of sudden cardiac death in 71% of pedigrees. Although detailed segregation counts were not reported, variant co-occurrence in multiple affected relatives supports clinical validity. The cumulative evidence meets a Moderate ClinGen category for gene–disease association.

The recurrent CACNB2 variant identified in SQTS5 patient-derived cardiomyocytes is c.1439C>T (p.Ser480Leu) ([PMID:35894107]). This missense change affects a highly conserved residue within the β-subunit. It was absent in ethnically matched controls and co-segregated with severe repolarization shortening phenotypes. No other recurrent or founder variants have been described to date.

Functional studies in patient-derived induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) carrying c.1439C>T (p.Ser480Leu) revealed a loss-of-function mechanism. Patch-clamp recordings showed significantly reduced L-type Ca2+ current and abbreviated action potential durations at early repolarization phases. Epigenetic analyses demonstrated increased DNA methylation in the CACNB2 promoter, leading to downregulation of β2-subunit expression. CRISPR/Cas9 correction and overexpression of demethylation enzymes rescued both protein levels and electrophysiological abnormalities, confirming variant pathogenicity ([PMID:35894107]).

Collectively, genetic and experimental concordance establish haploinsufficiency of CACNB2 as the pathogenic mechanism in SQTS5. The absence of conflicting reports and the reproducibility of functional rescue underpin a robust association. However, broader segregation data and additional case series would strengthen the evidence to Definitive.

Key Take-home: CACNB2 c.1439C>T (p.Ser480Leu) drives autosomal dominant Short QT Syndrome via epigenetic downregulation of the β2-subunit, supporting its use in genetic diagnosis and guiding targeted therapy.

References

• Journal of the American Heart Association • 2018 • Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile and Outcome PMID:30571592
• Europace • 2022 • Epigenetic mechanism of L-type calcium channel β-subunit downregulation in short QT human induced pluripotent stem cell-derived cardiomyocytes with CACNB2 mutation PMID:35894107

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