title: Left-dominant arrhythmogenic cardiomyopathy in a large family: associated desmosomal or nondesmosomal genotype?
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.
authors.affiliation: Department of Cardiology, University Medical Center Utrecht and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. J.Groeneweg-4@umcutrecht.nl
authors.forename: Judith A
authors.initials: JA
authors.lastname: Groeneweg
authors.forename: Paul A
authors.initials: PA
authors.lastname: van der Zwaag
authors.forename: Jan D H
authors.initials: JD
authors.lastname: Jongbloed
authors.forename: Moniek G P J
authors.initials: MG
authors.lastname: Cox
authors.forename: Arnold
authors.initials: A
authors.lastname: Vreeker
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: de Boer
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: van der Heijden
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.forename: Richard N W
authors.initials: RN
authors.lastname: Hauer
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000235:genetics; D003896:Desmosomes / Q000235:genetics; D004562:Electrocardiography / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D051191:Plakophilins / Q000235:genetics*; D011379:Prognosis; D018570:Risk Assessment; D012737:Sex Factors; D017180:Tachycardia, Ventricular / Q000235:genetics*
chemical_list: C495337:PKP2 protein, human; D051191:Plakophilins