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.
Methods and 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 V2 and V3 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.
Received December 20, 2005; revision received January 24, 2006; accepted January 27, 2006.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a disease with primarily right ventricular involvement that is characterized by fibrofatty infiltration of the myocardium and inflammatory infiltrates.1–7 The clinical presentation is highly variable but characterized mainly by ventricular arrhythmias, syncope, and sudden cardiac death (SCD) during various activities.1,5,8–16 Diagnosis may be difficult in individual cases but is facilitated by criteria proposed by a generally accepted consensus report (task force).17–20 These criteria are based on morphological, functional, and ECG features, in addition to family history.17 At least 50% of patients have affected relatives, suggesting a genetic basis for ARVC. The mode of inheritance is autosomal dominant with reduced and age-related penetrance.20–25
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Until recently, 5 loci and 4 potentially causative genes encoding plakoglobin (JUP), desmoplakin (DSP), transforming growth factor-β3 (TGFβ3), and the cardiac ryanodine receptor (RYR2) had been identified. However, only a small subset of ARVC patients showed mutations in these genes.26–29
The recent discovery of plakophilin-2 (PKP2) mutations in 32 of 120 probands (27%) with ARVC of western European descent suggests an important role of this gene in the pathogenesis of this disorder.30 PKP2, an armadillo-related protein, forms with other proteins, including plakoglobin and desmoplakin, an integral part of cardiac desmosomes. These major cell adhesion complexes link desmosomal cadherins with desmoplakin and the intermediate filament system, providing structural and functional integrity to adjacent cells.31 These structures are considered important for rigidity of cells and cell signaling.32–34 The exact pathogenesis of PKP2 mutations in ARVC is speculative, but cell-cell contact is believed to be impaired, leading to disruption of cardiomyocytes in response to mechanical stretch or stress, particularly in the so-called triangle of dysplasia (right ventricular outflow tract, inferobasal area, and apex).7,30
If the PKP2 mutations indeed occur as frequently as recently suggested, genetic screening would constitute an important tool in diagnosing persons at risk for this potentially life-threatening disorder. To evaluate this tool, screening of the PKP2 gene in a large cohort of Dutch ARVC patients referred to 4 tertiary referral centers throughout the Netherlands was performed. The goals of this study were to establish the prevalence and character of PKP2 mutations and to study phenotypic differences.
Clinical Evaluation and Diagnostic Criteria
Ninety-six white unrelated index patients were evaluated in 4 university hospitals in the Netherlands. A history was taken from all patients, and they were evaluated by physical examination, 12-lead ECG, 24-hour Holter monitoring, exercise testing, and 2-dimensional transthoracic echocardiography. In addition, 60 patients underwent MRI, 46 had nucleotide scintigraphy, 38 had a signal-averaged ECG, 72 underwent left and right ventricular cine angiography, 62 had an electrophysiological study, and 27 had a right ventricular endomyocardial biopsy.
The diagnosis of ARVC in index patients was established in accordance with criteria proposed by a task force.17 To verify the diagnosis, all patients were discussed by experienced cardiologists from the different centers in a consensus meeting. The onset of ARVC manifestations was defined as the age at which initial symptoms most likely related to ARVC emerged, including paroxysmal tachycardia, prolonged syncope, and successful resuscitation.
The local institutional review committees approved of the study. Informed consent was obtained from all participating patients.
The population consisted of 56 index patients (mean age at presentation, 35.2 years; 14 women) fulfilling the ARVC criteria:≥2 major criteria (n=20), 1 major and 2 minor criteria (n=34), or 4 minor criteria (n=2). In 34 of these index patients, additional family members had been clinically investigated to address the task force criteria. ARVC was considered proven familial when ≥1 additional family members were found to fulfill these criteria. Suspected familial ARVC was defined as having either 1 major and 1 minor or 3 minor criteria in another family member.
In addition, we tested 40 index patients with some ARVC features who did not fulfill the task force criteria.
DNA for PKP2 sequence analysis was isolated from peripheral blood samples according to standard protocols. Most patients were prescreened using denaturing gradient gel electrophoresis (DGGE) or denaturing high-performance liquid chromatography (DHPLC). Polymerase chain reaction products showing aberrant patterns by DGGE or DHPLC were reamplified and sequenced. DNA from a subset of patients was sequenced completely. The screening included all coding sequences but also 60 to 100 bp of flanking intronic sequences. Primers and conditions for DGGE and DHPLC are available on request; primers used for direct sequencing were obtained from Gerull et al.30 Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit (version 2.0) on a 3100 Genetic Analyzer (Applied Biosystems, Foster City, Calif) with SeqScape software (version 2.1.1, Applied Biosystems). If a novel mutation was identified, at least 150 ethnically matched control individuals were screened to recognize common polymorphisms. In 9 families (U2, U3, U4, U6, A3, M6, G1, G2, and G6), we were able to study the segregation of 6 different mutations because both clinical data and DNA from family members were available.
To determine whether the identical mutations found are recurrent or have a common founder, we performed haplotype analyses using 5 repeat markers within a region of 300 000 bp, including the entire genomic region of the PKP2 gene. For the positioning of the markers related to the human sequence, the August 2004 human reference sequence (NT_009714 region 25602762 to 25908664 bp), based on NCBI Build 35 version 1, was used. Primers used to amplify these markers are available on request. For each mutation that was found more than once, there was at least 1 index patient from which additional family members were available for haplotype analysis. This enabled the reconstruction of haplotypes and verification of the phase. Subsequently, these haplotypes were investigated in other index patients carrying the identical mutation.
Clinical characteristics in ARVC patients with and without a PKP2 mutation were compared by χ2 test. Values of P<0.05 were considered significant. All data were analyzed with the Statistical Package for Social Sciences (SPSS version 12.0; SPSS, Inc., Chicago, Ill).
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
Unique sequence variants were identified in 24 of 56 unrelated index patients fulfilling the ARVC criteria (43%) (Table 1 and Figure 1). One patient (U1) had 2 variants. Mutations were identified in 7 of 20 patients (35%) with ≥2 major criteria, 16 of 34 (47%) patients with 1 major and 2 minor criteria, and 1 of 2 patients with 4 minor criteria.
In the additional group of 40 patients not fulfilling the criteria, 2 mutations (c.397C>T and c.2386T>C) were identified (5%).
Four different mutations were found more than once: c.235C>T (5 index patients), c.397C>T (2 index patients), c.2386T>C (5 index patients), and c.2489+1G>A (3 patients). Of the 14 different mutations, 4 were missense, 7 were nonsense, 2 were insertion/deletion-frameshift, and 1 was a splice site mutation. Eleven of these were novel (Table 1 and Figure 1).
Pathogeneity of the Mutations Identified
Twelve of 14 sequence variants identified were considered to be disease causing because of change of charges or predicted major rearrangements of the protein. Moreover, they all affect highly conserved residues. Of the missense mutation c.76G>A (p.Asp26Asn) and the second mutation identified in patient U1, c.184C>A (p.Glu62Lys), the pathogeneity cannot be established with certainty because they were not located in highly conserved regions or amino acids, were located outside functional domains, or did not change the polarity of the amino acid involved. Until functional assays are available, these mutations have to be considered “unclassified variants.” None of the 14 variants identified were found in 300 control alleles, thus excluding the possibility of being a common polymorphism. In 9 patients, we studied the segregation of 6 different mutations in family members (c.235C>T in U2, G1, and G6; c.397C>T in A3 and U3; c.1211-1212insT in U4; c.1848C>A in G2; c.2544G>A in U6; and c.2489+1G>A in M6). No discordances were found; ie, affected family members also carried the identical mutation. Furthermore, we identified 2 missense mutations (c.209G>T [5 times] and c.2615C>T [2 times]) that were considered to be polymorphisms. The c.209G>T missense mutation was identified in 4 of 300 control alleles and did not segregate with the disease in relatives of patient U2, whereas the truncating mutation (Arg79X) in that family did. The c.2615C>T mutation is not located in a highly conserved region, nor does it lead to a substantial change in biochemical properties of the amino acid involved. Moreover, this mutation was identified in unrelated patients A3 and U3, both of whom also were carriers of a cosegregating truncating mutation (Gln133X).
Haplotype analyses revealed allele sharing among the patients carrying an identical mutation (including patients G7 [c.397C>T] and A10 [c.2386T>C] who did not meet the criteria). The shared alleles were identical in patients having the same mutation but were (largely) different between the different mutations. The most likely associated haplotypes in all index patients with the different identical mutations are represented in Tables 2 through 5⇓⇓⇓. These data suggest that the frequent mutations are from common founders rather than being recurrent.
Clinical Data and Comparison Between Mutation and Nonmutation Carriers
Index patients with established ARVC were referred because of ventricular tachycardia episodes (n=52), ventricular fibrillation (n=3), and SCD in a sibling with proven ARVC at autopsy (n=1). The age at initial presentation, diagnostic criteria, and follow-up of individual patients fulfilling the ARVC criteria are presented in Tables 6 and 7⇓ for PKP2 mutation carriers and patients without a PKP2 mutation. Comparing PKP2 mutation carrier and noncarrier ARVC patients showed no significant differences in terms of the average age at initial presentation, occurrence of familial sudden death, and characteristics according to the task force criteria, with the exception of negative T waves in V2 and V3 (in 23 of 24 mutation carriers versus 22 of 32 in noncarriers; P<0.05). In addition, no significant differences were noted in follow-up duration and number of implantable cardioverter-defibrillators (Table 8). In all patients with implantable cardioverter-defibrillator therapy, additional antiarrhythmic drug treatment was used. All other patients were treated only with drugs.
Finally, the occurrence of end-point events (documented sustained ventricular tachycardia episodes, ventricular fibrillation, appropriate implantable cardioverter-defibrillator therapy, successful resuscitation, and SCD) did not reach significance between groups.
Figure 2 is a flowchart of investigation of family members in relation to the yield of molecular analyses. Briefly, in 34 of the 56 index patients fulfilling the ARVC criteria, cardiologic evaluation of family members had been carried out previously. Twenty-three (68%) had familial ARVC (per-index-patient average, 3.1; range, 1 to 12 family members analyzed). In 11 index patients, no affected family members could be identified (average, 3.9; range, 1 to 9 family members per index patient analyzed).
In the absence of familial disease, no PKP2 mutations were identified, whereas in familial forms of ARVC, a PKP2 mutation was found in 16 of 23 index patients (70%) (P<0.001).
Prevalence and Spectrum of PKP2 Mutations in ARVC Patients
In the population studied, 14 different mutations were identified in 24 of 56 patients fulfilling the ARVC criteria (43%). Gerull et al30 identified 25 different mutations in 32 of 120 probands (27%) fulfilling the task force criteria. In both studies, the majority of mutations results in a truncated or aberrant protein as a result of insertion-deletion, nonsense, or splice site mutations. These results highlight the importance of the PKP2 gene in the pathogenesis of ARVC in the Dutch population.
The fact that 10 of 14 PKP2 mutations are predicted to result in a truncated protein product suggests a loss of function, resulting in haploinsufficiency. On the other hand, missense mutations giving amino acid substitutions most likely result in protein variants with defects in protein function(s) and/or instable protein products. Moreover, these nonfunctional variants might interfere with the function of the normal allele product. Because PKP2 has been shown to form an essential component of desmosomes, the functional consequences of mutations can be expected at the level of desmosome formation and consequential effects in cell-cell adhesion and signaling.31,33,34
Recurrent or Founder Mutations?
Three mutations from the initial study by Gerull et al30 were supposed to be recurrent (c.235C>T, c.2146-1G>C, and c.2203C>T, identified 6, 2, and 2 times, respectively) because no shared alleles were identified. Interestingly, one of their recurrent mutations (c.235C>T) was found 5 times in this study. In contrast to their results, our haplotype analyses did show allele sharing in all 5 index patients carrying this mutation, suggesting a common founder. It should be noted that in this study parental genotypes were only partially available as well. The occurrence of founder mutations in the Dutch population, also in inherited cardiologic disorders, is clearly recognized.35,36 The population reported by Gerull et al30 is likely to be more heterogeneous because they indicate it is from western European descent. In addition, for the c.397C>T, c.2386C>T, and c.2489+1C>A mutations that we identified 3, 6, and 3 times, respectively, our results suggest a founder rather than a recurrent mutation.
Penetrance and Variable Phenotypes
Hamid et al24 already recognized that 11% of relatives from ARVC index patients were found to have isolated minor cardiac abnormalities, most often T-wave inversion in the right precordial leads. These persons, however, did not fulfill the task force criteria. Given the mode of inheritance, Hamid et al suggested that the ECG abnormalities are likely to represent early disease. Nava et al37 also ascertained less severe clinical forms in family members with a more favorable outcome than previously thought. They also considered subtle ECG and echocardiographic abnormalities diagnostic for ARVC. Given the clinical variability and reduced and age-dependent penetrance of ARVC, the clinical criteria lack sensitivity in family members.24,37
This variable expression of the PKP2 gene also was confirmed in our additional patient group that did not fulfill the ARVC criteria because 2 ARVC-related mutations were identified in these 40 patients. Although the clinical course of the disease cannot be predicted from DNA analysis, it helps in identifying those persons at risk for developing disease-related symptoms. In those individuals, regular follow-up is advisable.
No specific genotype-phenotype correlation could be detected in the group of patients carrying a PKP2 mutation. This may be due to small sample size; however, given the intrafamilial variability, major genotype-phenotype correlations were not expected.24,37 Moreover, the presence or absence of a PKP2 mutation could not be related to age at onset, events during follow-up, or any specific clinical manifestation, except for negative T waves in V2 and V3 that were more frequently encountered in mutation carriers.
Regular screening of family members of the index patients was strongly advised and started years before the DNA analyses were initiated. Nevertheless, family members from 22 index patients fulfilling the ARVC criteria have not been evaluated for various reasons. In the other 34 patients, 114 additional family members underwent cardiological screening to evaluate manifestations of ARVC. In 70% of these index patients with affected family members, a PKP2 mutation was identified, whereas no mutations were found in 11 index patients in whom investigation of family members revealed no signs of ARVC (P<0.001). This high yield of mutations in familial ARVC underscores the importance of this gene in the pathogenesis of inherited forms of this disease. On the other hand, the absence of PKP2 mutations in nonfamilial ARVC cases suggests the possibility of a nongenetic origin, eg, myocarditis or alternatively a spontaneous mutation in another gene.38,39
Finally, all 5 index patients with familial ARVC and sudden death in family members <35 years of age appeared to be PKP2 mutation carriers.
Patients referred to tertiary referral centers probably reflect the more severe end of the disease spectrum; therefore, the population studied cannot be regarded as representative of the variable expression of the disease. The familial character of ARVC could be established only in family members who voluntarily agreed to cardiologic examination after genetic counseling. Different reasons, eg, psychological or socioeconomic, might underlie the choice to refrain from participation in screening, leading to a bias in family evaluation.
The evaluation and interpretation of data obtained after cardiologic investigation and interpretation of criteria may vary between different centers. To prevent this, consensus meetings were organized, with all centers participating.
In 15 ARVC patients (5 PKP2 mutation carriers, 10 noncarriers), the RYR2 gene was excluded as the causative gene. Because patients not carrying a PKP2 mutation and PKP2 mutation carriers might have mutations in other ARVC-related genes that have not been screened, this is a potential limitation. In DNA analysis, large rearrangements (duplications/deletions) of a gene can be missed by DGGE, DHPLC, or sequencing analysis. Besides, mutations in the promoter region of the gene cannot be excluded. Given the size of the control group, it cannot be completely excluded that a certain mutation represents a low-frequency polymorphism.
PKP2 mutations can be identified in nearly half of Dutch patients fulfilling the ARVC task force criteria. However, in familial ARVC, mutation detection increases up to 70% of patients, and even up to all cases of familial ARVC combined with a positive family history of premature SCD. This remarkably high yield of PKP2 mutations demonstrates its predominance in the genetic origin of ARVC and is unique in inherited cardiomyopathies. However, in nonfamilial ARVC, PKP2 mutations were absent, suggesting a different origin.
This study was made possible by a grant from the Netherlands Heart Foundation (2003B062). We thank Chantal Conrath, MD, PhD, for her support in collecting clinical data; Jan Jongbloed, Marcel Nelen, and Hennie Bikker for their interpretation of molecular data; and Marian Bakker for the statistical analyses.
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Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is most often an autosomal dominantly inherited cardiomyopathy with primarily right ventricular involvement. The clinical presentation is highly variable but characterized mainly by ventricular arrhythmias, syncope, and sudden cardiac death. Diagnosis is based on generally accepted criteria proposed by a task force. Recently, the plakophilin-2 gene (PKP2) has been discovered as a causative gene. The results of our study verify the importance of this gene in the origin of ARVC in that we identified mutations in 43% of ARVC patients. Several of the mutations were found more than once, and additional investigations suggest that they originate from common founders. Of 34 index patients, additional family members had been screened previously for signs of this disease. ARVC turned out to be familial in 23 patients (68%). In familial ARVC, most patients (70%) had a PKP2 mutation. This high yield is unique in inherited cardiomyopathies. Of 11 index patients with nonfamilial ARVC, however, none had a PKP2 mutation. Therefore, nonfamilial ARVC seems to be unrelated to PKP2 and may even have a different nongenetic cause such as myocarditis. Thus, ARVC is not a uniform disease. The results of this study shed light on the origin of ARVC and facilitate targeted DNA analysis in familial cases. This will allow early recognition of persons and families at risk for this potentially life-threatening disorder.