Abstract 11262: Dutch Phospholamban Founder Mutation Associated with Left-Dominant Arrhythmogenic Phenotype
Introduction: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is considered to be an inherited, primarily right ventricle (RV) disease due to desmosomal gene mutations. However, a left-dominant form has been described, among others due to PKP2 variant c.419C>T. Recently, a non-desmosomal Dutch founder mutation in the Phospholamban gene (PLN; c.40_42delAGA, p.Arg14del) has been identified causing either an ARVD/C or dilated cardiomyopathy phenotype.
Aim: Cosegregation analysis of PKP2 c.419C>T variant versus PLN c.40_42delAGA mutation.
Methods: A Dutch family (13 family members, median age 42, range 33-70 years) with ventricular tachycardia and heart failure underwent 1) meticulous phenotypic characterization and 2) DNA analysis of 5 known desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) and PLN.
Results: Fulfilment of 2010 Task Force Criteria (TFC) for ARVD/C in 6 family members (median age 55, range 40-70 years). Signs of left ventricle (LV) involvement (inverted T waves in V4-V6, LV wall motion abnormalities and late enhancement (n=4) and 1 reduced (32%) LV ejection fraction) in 7 family members (median age 46, range 40-70 years, including the 6 with proven ARVD/C). PKP2 c.419C>T was found as single variant in 3 family members and combined with PLN 40_42delAGA in 3 others. No other desmosomal gene mutations identified. PLN mutation was found in 9 family members, including the 6 with ARVD/C diagnosis and all 7 with LV involvement. PLN 40_42delAGA was found as single mutation in 6 family members (age 40, 40, 46, 46, 61 and 64 years) and combined with PKP2 419C>T in 3 others (age 42, 65 and 70 years). Recording of low voltage ECG (voltages <5mV in standard leads) in 4/9 PLN mutation carriers. None of the PKP2 single variant carriers (age 37, 42 and 42 years) showed any sign of RV or LV involvement.
Conclusion: PLN mutation cosegregates with ARVD/C diagnosis and with electrocardiographic and structural LV abnormalities. In this family no evidence of individual disease causing contribution of the single PKP2 c.419C>T variant.
- © 2011 by American Heart Association, Inc.