Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?

Heart Rhythm. 2013 Apr;10(4):548-59. doi: 10.1016/j.hrthm.2012.12.020. Epub 2012 Dec 25.

Abstract

Background: Arrhythmogenic cardiomyopathy (AC) is considered a predominantly right ventricular (RV) desmosomal disease. However, left-dominant forms due to desmosomal gene mutations, including PKP2 variant c.419C>T, have been described. Recently, a nondesmosomal phospholamban (PLN) mutation (c.40_42delAGA) has been identified, causing dilated cardiomyopathy and arrhythmias.

Objective: To gain more insight into pathogenicity of the PKP2 variant c.419C>T by cosegregation analysis of the PKP2 variant c.419C>T vs the PLN mutation c.40_42delAGA.

Methods: A Dutch family (13 family members, median age 49 years, range 34-71 years) with ventricular tachycardia underwent (1) meticulous phenotypic characterization and (2) screening of 5 desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) and PLN.

Results: Six family members fulfilled 2010 AC Task Force Criteria. Seven had signs of left ventricular (LV) involvement (inverted T waves in leads V4-V6, LV wall motion abnormalities and late enhancement, and reduced LV ejection fraction), including 6 family members with proven AC. The PKP2 variant c.419C>T was found as a single variant in 3 family members, combined with the PLN mutation c.40_42delAGA in 3 others. PLN mutation was found in 9 family members, including the 6 with AC and all 7 with LV involvement. The PLN mutation c.40_42delAGA was found as a single mutation in 6, combined with the PKP2 variant c.419C>T in 3 others. A low-voltage electrocardiogram was seen in 4 of 9 PLN mutation-positive subjects. None of the family members with the single PKP2 variant showed any sign of RV or LV involvement.

Conclusions: The PLN mutation c.40_42delAGA cosegregates with AC and with electrocardiographic and structural LV abnormalities. In this family, there was no evidence of disease-causing contribution of the PKP2 variant c.419C>T.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Arrhythmogenic Right Ventricular Dysplasia / diagnosis
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Cardiomyopathy, Dilated / diagnosis
  • Cardiomyopathy, Dilated / genetics
  • Desmosomes / genetics
  • Electrocardiography / methods
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing / methods
  • Genotype
  • Heterozygote*
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Plakophilins / genetics*
  • Prognosis
  • Risk Assessment
  • Sex Factors
  • Tachycardia, Ventricular / genetics*

Substances

  • PKP2 protein, human
  • Plakophilins