Abstract 16035: Epidemiological Evidence Suggests CAV3 T78M Should be Considered a Benign Polymorphism and not an Independent, Multi-Disease-Susceptibility Mutation
INTRODUCTION: CAV3 T78M has been reported to be a proarrhythmic mutation associated with Long QT Syndrome (LQTS) and other diseases. The purpose of this study was to determine if CAV3 T78M is a pathogenic mutation or just background “genetic noise” unlikely to cause disease.
METHODS: The frequency of CAV T78M was compared between 850 unrelated patients referred for FAMILION® LQTS genetic testing and 405 ethnically-diverse, presumed healthy controls. In addition, prior published reports on CAV3 T78M were pooled and evaluated holistically.
RESULTS: CAV3 T78M was detected in five cases (0.6%) referred for LQTS genetic testing, one of whom also hosted a known pathogenic mutation in KCNQ1. By comparison, one Asian control and one Caucasian control (0.5%) hosted CAV3 T78M (p = 1.0). A review of the published literature revealed CAV3 T78M has been reported at similar, low frequency both in patients with various diseases (e.g., LQTS, DCM, idiopathic hyper-CK-emia, and SIDS) and in different control populations of presumed healthy individuals (e.g., 3 of 630 individuals of diverse ancestry in the August 2010 release of the 1000 Genomes Project database).
CONCLUSIONS: Detection of CAV3 T78M in unrelated patients with various diseases has led to its repeated labeling as pathogenic in the literature. However, these observations and limited in vitro characterization are not sufficient to conclude that CAV T78M is pathogenic. Instead, we observe that CAV3 T78M is present in about 0.5% of both cases and controls. Based on this epidemiological evidence, we conclude that CAV3 T78M is not an independent, multi-disease-susceptibility mutation and is most likely a benign polymorphism. Our observations underscore the importance of careful scrutiny and large, diverse control populations for distinguishing disease-causing mutations from otherwise innocuous, rare genetic variants in rare diseases such as LQTS.
- © 2011 by American Heart Association, Inc.