Abstract 15725: Next-generation-based Mutation Screening Identifies A Dysfunctional Calcium Channel β-subunit Mutation In Short QT Syndrome
Short QT syndrome (SQTS) is a rare familial disease with susceptibility to atrial and ventricular fibrillation. Gain of function mutations in KCNQ1 , KCNH2 , and KCNJ2 cause isolated SQTS, and mutations in L-type calcium channel α and β-subunit genes have been reported in patients with Brugada syndrome and short QT intervals. We studied a 10 year old boy after the witnessed sudden death of his healthy 11 year-old brother. The boy's ECG (Figure, panel A) showed an absent ST segment and unusually tall, peaked T-waves. The QT was constant at 320 ms despite reflex bradycardia to <60 bpm induced with phenylephrine, and procainamide challenge did not elicit a Brugada phenotype. Effective refractory periods were 160 ms (atrial) and 190 ms (ventricle), with inducible atrial fibrillation but no induced ventricular arrhythmias. Sequencing KCNQ1 , KCNH2 , and KCNJ2 found no mutations. We then used a custom array on the Nimblegen platform to capture exon and flanking sequence in 79 high priority arrhythmia genes, encompassing 305 kb. Sequencing using the Illumina Gene Analyzer II identified previously unreported variants, including D627E in CACNB2 , confirmed by Sanger sequencing. This is a conservative change in the amino acid structure, predicted to not alter function. However, when co-transfected in CHO cells with CACNA1C , it generated reduced peak ICa and strikingly slowed voltage-dependent inactivation; coexpression with wild-type β-subunits revealed no dominant negative effect (Figure, Panels B and C). We conclude that the spectrum of CACNB2 –related mutations includes pure SQTS. Next-generation sequencing coupled to function will be a valuable tool for studying familial arrhythmia disease.
- © 2010 by American Heart Association, Inc.