Abstract 1929: Mutations in the Cardiac L-Type Calcium Channel Associated With Four Sudden Cardiac Death Syndromes
Mutations in the Cardiac L-Type Calcium Channel Associated with Inherited Sudden Cardiac Death Syndromes
Background: L-Type Calcium Channel (LTCC) mutations have been associated with Timothy (LQT8), Brugada (BrS) and Short QT (SQTS) syndromes. Little is known about the extent to which mutations in the various subunits of LTCC contribute to these various phenotypes. This study sought to identify mutations in the α1, β2 & α2β subunits of LTCC among probands diagnosed with BrS, LQTS, idiopathic ventricular fibrillation (IVF) and early repolarization syndrome (ERS).
Methods: All exons and intron borders of CACNA1C, CACNAB2b and CACNA2D1 including alternative exons were screened by direct sequencing. Two probands diagnosed with LQT8, 156 with BrS, 8 with ERS and 21 with IVF were genotyped. Variants were probed in 100 –300 ethnically-matched healthy controls.
Results: Overall, 24 distinct mutations (22 missense and 2 insertion/deletion) were identified (Figure⇓). A total of 11.5% of BrS probands displayed mutations in α1 (6.4%) β2 (4.5%) α2β (0.64%) subunits of LTCC; 100% of LQT8 patients had mutations in the α1 subunit; 9.5% of IVF patients had mutations in the α1 and 11% in the β2 subunit; 12.5% of ERS patients had mutations in the β2 subunit. Most mutations were missense and were concentrated in the C terminus and interdomain linker regions.
Conclusion: Mutations in the L-type calcium channels are detected in a relatively high percentage of probands with inherited cardiac arrhythmia syndromes, suggesting that genetic screening of Cav genes may prove to be a helpful diagnostic tool.