Plakophilin-2 mutations are the major determinant of familial arrhythmogenic right ventricular dysplasia/cardiomyopathy.
BACKGROUND
Mutations in the plakophilin-2 gene (PKP2) have been found in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC). Hence, genetic screening can potentially be a valuable tool in the diagnostic workup of patients with ARVC.


RESULTS
To establish the prevalence and character of PKP2 mutations and to study potential differences in the associated phenotype, we evaluated 96 index patients, including 56 who fulfilled the published task force criteria. In addition, 114 family members from 34 of these 56 ARVC index patients were phenotyped. In 24 of these 56 ARVC patients (43%), 14 different (11 novel) PKP2 mutations were identified. Four different mutations were found more than once; haplotype analyses revealed identical haplotypes in the different mutation carriers, suggesting founder mutations. No specific genotype-phenotype correlations could be identified, except that negative T waves in V(2) and V(3) occurred more often in PKP2 mutation carriers (P<0.05). Of the 34 index patients whose family members were phenotyped, 23 familial cases were identified. PKP2 mutations were identified in 16 of these 23 ARVC index patients (70%) with familial ARVC. On the other hand, no PKP2 mutations at all were found in 11 probands without additional affected family members (P<0.001).


CONCLUSIONS
PKP2 mutations can be identified in nearly half of the Dutch patients fulfilling the ARVC criteria. In familial ARVC, even the vast majority (70%) is caused by PKP2 mutations. However, nonfamilial ARVC is not related to PKP2. The high yield of mutational analysis in familial ARVC is unique in inherited cardiomyopathies.
Department of Clinical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. p.van.tintelen@medgen.umcg.nl
J Peter
JP
van Tintelen
Mark M
MM
Entius
Zahurul A
ZA
Bhuiyan
Roselie
R
Jongbloed
Ans C P
AC
Wiesfeld
Arthur A M
AA
Wilde
Jasper
J
van der Smagt
Ludolf G
LG
Boven
Marcel M A M
MM
Mannens
Irene M
IM
van Langen
Robert M W
RM
Hofstra
Luuk C
LC
Otterspoor
Pieter A F M
PA
Doevendans
Luz-Maria
LM
Rodriguez
Isabelle C
IC
van Gelder
Richard N W
RN
Hauer
D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D051191:Plakophilins / Q000235:genetics*
C495337:PKP2 protein, human; D051191:Plakophilins