Abstract 15855: A Novel Mutation (D538E) in CACNB2b Associated with Infant Brugada Syndrome
Introduction: Brugada syndrome (BrS) is an inherited sudden cardiac death syndrome characterized by ST segment elevation in the right precordial ECG leads and the development of polymorphic ventricular tachycardia. Mutations in the calcium channel are known to be associated with BrS and a shorter than normal QT interval. This study examines the hypothesis that mutations causing a simultaneous loss of function of ICa and IKs can give rise to BrS with a normal QTc at a young age.
Methods: Fourteen candidate genes were screened by direct sequencing of all exons and intron borders. Ion channel variants were cloned by site-directed mutagenesis, expressed in TSA201 cells and studied electrophysiologically using patch clamp techniques.
Results: A male with no previous history of heart disease, experienced complete loss of consciousness at 13 months and 2.5 years of age. A coved-type ST segment elevation was observed in the right precordial leads immediately upon resuscitation. EP testing was negative. A novel genetic variation in the CACNB2b, the gene that encodes the β subunit of the L-type calcium channel, was identified in a highly conserved residue. The D538E-CACNB2b variant was absent in 484 reference control alleles. The proband was also found to have a D76N mutation in KCNE1 and a rare polymorphism G463S in KCNQ1. Wild-type (WT) or mutant CACNB2b was homozygously co-expressed with WT-CACNA1C and WT-CACNA2D1 in TSA201 cells. At 0 mV, peak ICa density was reduced by 73 % in mutant vs. WT channels (n=7; p <0.001). The KCNQ1 and KCNE1 variants were previously shown to reduce IKs by 40-50%. Whereas the calcium channel variation is expected to abbreviate the QT interval, the potassium channel variations are expected to prolong the QT interval. These opposing changes explain the appearance of BrS phenotype with a normal QT interval.
Conclusions: Our results suggest that loss of function in ICa by a genetic mutation in CACNB2b can result in an infant BrS phenotype in which the QT interval is not abbreviated because it is accompanied by another genetic mutation leading to a loss of function in IKs.
- © 2010 by American Heart Association, Inc.