CAV3 and Long QT Syndrome

CAV3 has been implicated in type 9 long QT syndrome (LQT9) through rare heterozygous missense variants. A 39-year-old female presenting with drug-induced sudden cardiac arrest and extreme QTc prolongation (>600 ms) was found to carry a CAV3 V37L (c.109G>C (p.Val37Leu)) variant, with no family history or segregation data reported (PMID:32387251). Large LQTS cohorts and gene curation efforts have rarely identified pathogenic CAV3 variants, and an evidence-based reappraisal classified CAV3 among genes with limited/disputed causality for congenital LQTS (PMID:31983240).

Functional studies in TSA201 cells and hiPSC-derived cardiomyocytes demonstrated that V37L spared Nav1.5 late current but produced a 1.5-fold increase in peak ICa,L with slower inactivation, a 74.9 % decrease in IKs peak density, a 31.1 % decrease in IKr peak density, and marked prolongation of action potential duration (PMID:32387251). These data support a combined gain-of-function in ICa,L and loss-of-function in IKs and IKr as a mechanistic basis for QT prolongation. However, the single-patient observation without segregation, rarity of CAV3 variants in LQTS panels, and absence of replication yield a ClinGen gene–disease validity of Limited. Key take-home: CAV3 variants such as V37L can perturb repolarization reserve but require additional genetic confirmation before incorporation into routine LQTS diagnostic testing.

References

• International journal of cardiology • 2020 • Discovery and characterization of a monogenetic insult, caveolin-3-V37L, that precipitated oligo-proteomic perturbations governing repolarization reserve. PMID:32387251
• Circulation • 2020 • An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. PMID:31983240

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