Abstract 13608: Presence of Short Qt Identifies Brugada Syndrome Patients With Higher Yield of Cacna1c Mutations: Implications for Genotyping Strategies
Loss of function mutations in the CACNA1C gene encoding the alpha subunit of the cardiac L-type calcium channel have been identified in patients (pts) showing an overlapping phenotype encompassing Brugada Syndrome (BrS) and Short QT Syndrome (SQTS). We screened for CACNA1c mutations 26 pts with SQTS (QTc360. All patients were negative to the screening of SCN5A and GPD1L BrS genes. CACNA1c full lenght open reading frame was screened by direct sequencing. A sequence homology tool (SIFT) was employed to predict the damaging effect of each mutation. A score =0 indicates that a mutationis likely to disrupt protein function, while higher scores (up to the value of 1) are less likely to cause disruptive changes. We consider pathogenic only mutations with a score = 0. Eight novel non synonimous missense mutations (6 with a SIFT score= 0, 1with score=0.3 and 1 with score= 0.6) were identified. Four mutations occurred in the 26 SQTS patients (mean QTc 327 ± 14): all of them had a SIFT score=0. The remaining 4 mutations were identified in the 168 BrS pts with a QTc >360 msec. Overall the prevalence of CACNA1c mutations was 15% among pts with SQTS and BrS. Among patients with BrS and QTc>360msec 4 mutations were identified (prevalence of 2.3% p<0.01 vs SQTS and BrS) but only 2 of them were considered pathogenic according to SIFT score (prevalence 1.1%; p< 0.003 vs SQTS andBrS). Cost per positive genotyped patient using pricing of commercially available genotyping in USA was 29000 $ in SQTS and BrS pts while it was 749000 $ in BrS pts with normal QTc. Our data suggest that the global yield of CACNA1c genetic screening in BrS/SQT +BrS is approximately of 4%; the presence of a short QT (QTc<360) associated with a Brugada Syndrome phenotype identifies a subgroup of patients with a high prevalence of CACNA1c mutations, comparable to the presence of SCN5A mutations in BrS. In a tiered approach to BrS genotyping, the presence of QTc<360 associated with BrS phenotype is likely to be a valuable element for cost containment and selection of patients to be tested on CACNA1c gene.
- © 2011 by American Heart Association, Inc.