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Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Synonyms: ARVC, ARVD, Arrhythmogenic Right Ventricular Cardiomyopathy, Arrhythmogenic Right Ventricular Dysplasia

, MD, PhD, , MS, and , MS, CGC.

Author Information
, MD, PhD
Section of Cardiology
University of Chicago
Chicago, Illinois
, MS
Section of Cardiology
University of Chicago
Chicago, Illinois
, MS, CGC
Section of Cardiology
University of Chicago
Chicago, Illinois

Initial Posting: ; Last Update: January 9, 2014.

Summary

Disease characteristics. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).

Diagnosis/testing. The diagnosis of ARVD/C is made using a combination of noninvasive and invasive tests to evaluate cardiac structure and rhythm. The eight genes known to be associated with ARVD/C are: TGFB3 (locus name: ARVD1), RYR2 (ARVD2), TMEM43 (ARVD5), DSP (ARVD8), PKP2 (ARVD9), DSG2 (ARVD10), DSC2 (ARVD11), and JUP (ARVD12). Four additional genes associated with ARVD/C have been mapped but not identified (locus names ARVD3, ARVD4, ARVD6, and ARVD7). Additional loci remain undetermined.

Management. Treatment of manifestations: Management is individualized and focused on prevention of syncope, cardiac arrest, and sudden death through use of antiarrhythmic medication, implantable cardioverter-defibrillators, and (rarely) heart transplantation. Individuals with clinical signs of right heart failure and/or left ventricular dysfunction and a history of ventricular tachycardia should be treated aggressively.

Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives in families in which the disease-causing mutation is known: those with the family-specific mutation warrant annual clinical screening of cardiac function and rhythm between ages ten and 50 years. If genetic testing has not been performed or did not identify a disease-causing mutation in an affected family member, clinical screening is recommended for asymptomatic at-risk first-degree relatives every three to five years after age ten years.

Genetic counseling. ARVD/C is typically inherited in an autosomal dominant manner. A proband with autosomal dominant ARVD/C may have the disorder as a result of a de novo mutation. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with autosomal dominant ARVD/C has a 50% chance of inheriting the mutation. ARVD/C may also be inherited in a digenic manner (i.e., one ARVD/C-causing mutation in each of two genes). Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation(s) have been identified in the family.

Diagnosis

Diagnostic Criteria

Diagnostic criteria for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), initially proposed by an International Task Force [McKenna et al 1994], were revised by Marcus et al [2010] (see full text) to incorporate new knowledge and technology to improve diagnostic sensitivity while maintaining diagnostic specificity. Individuals are classified as having a definite, borderline, or possible diagnosis of ARVD/C.

Definite diagnosis of ARVD/C:

  • Two major criteria or
  • One major and two minor criteria or
  • Four minor criteria from different categories

Borderline diagnosis of ARVD/C:

  • One major criteria and one minor or
  • Three minor criteria from different categories

Possible diagnosis of ARVD/C:

  • One major criteria or
  • Two minor criteria from different categories

Global and/or Regional Dysfunction and Structural Alterations

Major

  • By 2D echo
    • Regional RV akinesia, dyskinesia, or aneurysm

      AND
    • ONE of the following (end diastole):
      • PLAX (parasternal long axis) RVOT (right ventricular outflow tract) ≥32 mm (corrected for body surface area [PLAX/BSA] ≥19 mm/m2)
      • PSAX (parasternal short axis) RVOT ≥36 mm (corrected for body surface area [PSAX/BSA] ≥21 mm/m2)
      • Fractional area change ≤33%
  • By MRI
    • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction

      AND
    • ONE of the following:
      • Ratio of RV end-diastolic volume to BSA ≥110mL/m2 (male) or ≥100 mL/m2 (female)
      • RV ejection fraction ≤40%
  • By right ventricular angiography. Regional RV akinesia, dyskinesia or aneurysm

Minor

  • By 2D echo
    • Regional right ventricular akinesia or dyskinesia

      AND
    • ONE of the following (end diastole):
      • PLAX RVOT ≥29 to <32 mm (corrected for body surface area [PLAX/BSA] ≥16 to <19 mm/m2)
      • PSAX RVOT ≥32 to <36 mm (corrected for body surface area [PSAX/BSA] ≥18 to <21 mm/m2)
      • Fractional area change >33 to ≤40%
  • By MRI
    • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction

      AND
    • ONE of the following:
      • Ratio of RV end-diastolic volume to BSA ≥100 to <110 mL/m2 (male) or ≥90 to <100 mL/m2 (female)
      • RV ejection fraction >40% to ≤45%

Tissue Characterization of Walls

Major. Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of the RV free wall myocardium in at least one sample, with or without fatty replacement of tissue on endomyocardial biopsy

Minor. Residual myocytes 60% to 75% by morphometric analysis (or 50%-65% if estimated), with fibrous replacement of the RV free wall myocardium in at least one sample, with or without fatty replacement of tissue on endomyocardial biopsy

Repolarization Abnormalities

Major. Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in individuals age >14 years (in the absence of complete right bundle branch block QRS ≥120ms)

Minor

  • Inverted T waves in leads V1 and V2 in individuals >14 years of age (in absence of complete right bundle branch block) or in V4, V5, or V6.
  • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block

Depolarization/Conduction Abnormalities

Major. Epsilon waves (reproducible low-amplitude signals between end of QRS complex to onset of the T wave) in the right precordial leads (V1 to V3)

Minor

  • Late potential by signal-averaged ECG (SAECG) in at least one of three parameters in the absence of a QRS duration of ≥110 ms on the standard ECG
  • Filtered QRS duration (fQRS) ≥114 ms
  • Duration of terminal QRS <40 uV (low amplitude signal duration) ≥38 ms
  • Root-mean-square voltage of terminal 40 ms ≤20 uV
  • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R’, in V1, V2, or V3 in the absence of complete right bundle branch block

Arrhythmias

Major. Nonsustained or sustained ventricular tachycardia of left bundle branch morphology with superior axis (negative or indeterminate QRS in leads II, III and aVF and positive in lead aVL)

Minor

  • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle-branch block morphology with inferior axis (positive QRS in leads II, III and aVF and negative in lead aVL) or of unknown axis
  • >500 ventricular extrasystoles per 24 hours (Holter)

Family History

Major

Minor

Additional Information beyond the Diagnostic Criteria

Note: The phenotype of ARVD/C is widely variable and some affected individuals may not meet either the strict criteria outlined in McKenna et al 1994 [Nava et al 2000, Hamid et al 2002, Gerull et al 2004] or the more current Marcus et al [2010] criteria; however, such individuals may still be at risk for cardiovascular events including arrhythmias and, therefore, warrant continuing care by a cardiologist.

Of note, additional considerations regarding the noninvasive and invasive tests of cardiac structure and rhythm described above are outlined below.

Noninvasive Testing

ECG changes may develop over time; therefore, individuals suspected of having ARVD/C who do not show these changes should undergo serial ECGs [Quarta et al 2010].

Echocardiography

  • 3D echocardiography, an experimental imaging modality, may be useful in diagnosis, as right ventricular myocardial mechanics such as velocity, displacement, strain, and strain rate can be better assessed with 3D echocardiography than with conventional 2D echocardiography [Teske et al 2007]. However, interpretation is variable based on the center's expertise in reading 3D echocardiograms; guidelines have not been established.
  • 3D echocardiography can be considered for persons with defibrillators for whom cardiac MRI is contraindicated [Prakasa et al 2006].

Cardiac MRI

  • MRI images demonstrating ARVD are included in Murphy et al [2010].
  • Cardiac MRI analysis should also include assessment of global and regional right ventricular function and right ventricular myocardial fibrosis.
  • Not all centers are experienced in the diagnosis of ARVD by cardiac MRI. Because identification of right ventricular free wall thinning and fatty infiltration on cardiac MRI in persons with a mild ARVD phenotype can be subject to a high degree of intra-observer variability, cardiac MRI is best performed in centers with experience.
  • Data are not yet available to guide evaluation of at-risk family members using cardiac MRI [Sen-Chowdhry et al 2006].
  • Cardiac MRI has not been able to detect early changes of ARVD in children; however, this could result from the absence of manifestations in children rather than a failure of the method [Fogel et al 2006]. Further studies are needed.

Invasive Testing

  • Electrophysiologic (EP) study findings. Ventricular tachycardia easily induced with ventricular pacing and extrastimulation
  • Right ventricular angiography (RVA) findings. Enlarged right ventricle with segmental abnormalities
  • Right ventricular endomyocardial biopsy findings. Fibrofatty replacement of the myocardium (predominantly in the apex, right ventricular outflow tract, and right ventricular inflow tract) and/or atrophy of the right ventricular myocardium

    Note: (1) The biopsy must sample an affected region to be diagnostic. (2) Recent studies have demonstrated a possible role for immunohistochemical staining of the myocardium for intercalated disk proteins [Asimaki et al 2009]; however, further studies are needed [van Tintelen & Hauer 2009b].
  • 3D electroanatomic voltage mapping maps low voltage areas of the right ventricle that correlate with fibrofatty replacement [Corrado et al 2005]. This method is still experimental.

Molecular Genetic Testing

The eight genes in which mutations are known to cause ARVD/C are TGFB3, RYR2, TMEM43, DSP, PKP2, DSG2, DSC2, and JUP. See Table 1.

Note: Five of the genes (DSP, PKP2, DSG2, DSC2, and JUP) encode proteins that are important to desmosome structure/function and may be referred to as ‘desmosomal genes’ in this GeneReview.

Evidence for additional locus heterogeneity includes as-yet undetermined loci/genes as well as the following loci for which no genes have yet been identified:

Note:

(1) Guidelines for genetic testing recommendations are available [Hershberger et al 2009]. The Heart Rhythm Society/European Heart Rhythm Association published an Expert Consensus Statement for genetic testing for cardiomyopathies [Ackerman et al 2011].

(2) The overall yield of genetic testing for all available genes in probands who meet the revised Task Force criteria [Marcus et al 2010] approximates 50% [Quarta et al 2011]. Thus, if molecular genetic testing does not identify a disease-causing mutation in an individual who meets diagnostic criteria, the clinical diagnosis of ARVD/C is unchanged.

(3) Because of the complexity of interpreting genetic testing results (see also Natural History), Ackerman et al [2011] note that extreme caution should be taken in interpreting results. Consideration should be given to referring patients to specialty centers to perform the genetic testing.

(4) Because of a significant level of reduced penetrance (see Penetrance), it may be appropriate to offer molecular genetic testing to simplex cases (i.e., a single occurrence of the clinical diagnosis of ARVD/C in a family).

(5) Molecular genetic testing should be considered in individuals who are suspected of having ARVD/C based on criteria of the International Task Force [Marcus et al 2010], but who do not meet criteria for a definite clinical diagnosis. For some of these individuals, identification of a disease-causing mutation in one of the ARVD/C-related genes fulfills the remaining criteria.

(6) Although mutations in some ARVD/C-related genes are more prevalent than others (Table 1), molecular genetic testing for all ARVD/C-related genes should be performed simultaneously (usually as part of a multi-gene panel) because up to 57% of persons with ARVD/C have been shown to have compound heterozygosity or digenic heterozygosity (see Natural History for more detailed description) [Barahona-Dussault et al 2010, Bauce et al 2010, Christensen et al 2010b, Xu et al 2010, Nakajima et al 2012]. Because ARVD/C multi-gene panels vary by methods used and genes included, the ability of a panel to detect a causative mutation(s) in any given individual also varies.

(7) Genetic testing is also warranted in those who otherwise meet criteria of the Task Force [McKenna et al 1994, Marcus et al 2010] in order to identify the causative mutation and enable genetic testing of at-risk family members (see Management and Genetic Counseling).

Table 1. Summary of Molecular Genetic Testing Used in Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy

Gene 1
(Locus Name)
Proportion of ARVD/C Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
PKP2
(ARVD9)4
Overall populations (Netherlands, USA, Canada, UK, Denmark, Italy, France, Switzerland): 22.6% 2

10%-52% (<10% in UK, Greece/Cyprus; 39%-52% in Netherlands, USA, China) 2
Mutation scanning / sequence analysis 4Sequence variants 5
2.8%Deletion/duplication analysis 6Exonic and whole-gene deletions/duplications 7
DSG2
(ARVD10)
3%-19%Mutation scanning / sequence analysis 4Sequence variants 5
Deletion/duplication analysis 6Exonic and whole-gene deletions/duplications; none reported to date
DSP
(ARVD8)
1%-16%Mutation scanning / sequence analysis 4Sequence variants 5
Deletion/duplication analysis 6Exonic and whole-gene deletions/duplications; none reported to date
DSC2
(ARVD11)
1%-13%Mutation scanning / sequence analysis 4Sequence variants 5
Deletion/duplication analysis 6Exonic and whole-gene deletions/duplications; none reported to date
RYR2
(ARVD2)
RareMutation scanning / sequence analysis 4Sequence variants 5
Deletion/duplication analysis 6Exonic and whole-gene deletions, none reported to date
TGFB3
(ARVD1)
RareMutation scanning / sequence analysis 4Sequence variants 5
Deletion/duplication analysis 6Exonic and whole-gene deletions/duplications; none reported to date
JUP
(ARVD12)
RareMutation scanning / sequence analysis 4Sequence variants 5
Deletion/duplication analysis 6Exonic and whole-gene deletion/duplications; none reported to date
TMEM43
(ARVD5)
UnknownMutation scanning / sequence analysis 4Sequence variants 5
Deletion/duplication analysis 6Exonic and whole-gene deletions/duplications; none reported to date

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. From Jacob et al [2012], a comprehensive overview of all published studies to date to yield overall population prevalence of the gene in which mutations are identified

3. See Molecular Genetics for information on allelic variants.

4. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably between laboratories based on the specific protocol used.

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. La Gerche et al [2010], Limura et al [2013], Roberts et al [2013]

Clinical Description

Natural History

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a myocardial disorder that predominantly affects the right ventricle. ARVD/C is a progressive disorder characterized by fibrofatty replacement of the myocardium, predisposing to ventricular tachycardia and sudden death in young individuals and athletes [Marcus et al 1982, Thiene et al 1988, Corrado et al 1998, Fontaine et al 1998]. The disease often affects the right ventricular apex, the base of the right ventricle, and the right ventricle outflow tract. The arrhythmias in ARVD/C most frequently arise from the right ventricle and have a left bundle branch block morphology.

Pathology in ARVD/C may also extend to involve the left ventricle [Horimoto et al 2000, Hamid et al 2002]. A recent study of cardiac MRI findings revealed that despite preserved global left ventricular function, regional left ventricular dysfunction was seen in people with ARVD/C [Jain et al 2010]; larger studies are needed to validate this finding.

The most common presenting symptoms are heart palpitations, syncope, and death. The four described phases of ARVD/C are: (1) concealed phase (no clinical manifestations of ARVD/C, but potential risk of sudden cardiac death); (2) an overt electrical disorder (characterized by symptomatic arrhythmias); (3) right ventricular failure; and (4) a biventricular pump failure (resembles dilated cardiomyopathy) [Dalal et al 2005]. Left ventricle involvement can occur at any of the above stages [Sen-Chowdhry et al 2007].

In a long-term study of 132 living affected individuals from 37 families, none were diagnosed in infancy and two were diagnosed at ages four and six years [Nava et al 2000]. The mean age at diagnosis was 31 years (±13; range: 4-64 years).

The principal characteristic of arrhythmogenic cardiomyopathies is the tendency for ventricular arrhythmia and sudden death in the absence of overt ventricular dysfunction. The increased risk for sudden death in ARVD/C is thought to relate to sudden ventricular arrhythmias.

A gender bias was identified with those with mutations in PKP2 (ARVD9). Among individuals with a heterozygous PKP2 mutation, 67% of males (compared to 35% of females) met Task Force criteria for diagnosis [McKenna et al 1994]; however, gender differences in age of diagnosis or survival were not significant [Dalal et al 2006]. Note that these findings may not be applicable to other genetic forms of ARVD/C.

Studies that have investigated the propensity to arrhythmia in ARVD include the following:

  • The risk of sudden death from ARVD/C is controversial [Firoozi et al 2003, Tabib et al 2003]. In a study of 160 probands fulfilling clinical criteria for ARVD/C, 24 died during follow-up giving an overall mortality rate of 18.5% and an annual mortality rate of 2.3% [Hulot et al 2004]. Mean age at death (±SD) was 54 years (±19). Of the 24 deaths, 21 were cardiovascular deaths, among which seven were sudden cardiac deaths and 14 were a result of progressive heart failure (7 ventricular tachycardia or fibrillation occurring during an acute episode of severe cardiac failure, 5 terminal heart failure, and 2 rapid deaths after cardiac transplantation) [Hulot et al 2004].
  • Lemola et al [2005] reported that of 24 persons with ARVD/C who received an implantable cardioverter-defibrillator (ICD), ten received appropriate shocks, four had inappropriate shocks, three had a heart transplant, one died of heart failure, and one died suddenly despite delivery of several device charges. The authors note that not every ICD discharge may be associated with an arrhythmia leading to sudden death; some arrhythmias occur in normal cardiac function and, therefore, the denotation of "appropriate shocks" may be misleading.
  • In a study of 100 persons with ARVD/C (diagnosed clinically or via autopsy), 31 experienced sudden cardiac death [Dalal et al 2005]. Of those diagnosed with ARVD/C while living, the death-free survival rate was 94% in persons older than age 60 years (mainly as a result of receiving ICDs to prevent sudden cardiac death).
  • In a long-term study of 11 families with mutations in TMEM43, Hodgkinson et al [2005] found that 50% of males considered at high risk for sudden death associated with ARVD/C died by age 39 years and 50% of females considered at high risk died by age 71 years. Mortality in these families was reduced by 28% in males who received an ICD. In another study of 137 persons in 15 families, males had a median age of disease onset of 32 years and females 44 years [Merner et al 2008]. Penetrance was 100% by age 63 years in males and age 76 years in females. In this study, the relative risk of dying of sudden cardiac death was 6.8 times greater in affected males than affected females.

ARVD/C is present in 4% to 22% of athletes with sudden cardiac death [Corrado et al 2003, Maron et al 2009]. There is some debate over whether high-intensity endurance exercise can cause development of ARVD/C.

  • La Gerche et al [2010] studied athletes with a history of arrhythmias of right ventricular origin to determine if they met the 1994 Task Force criteria [McKenna et al 1994], for ARVD/C. Sequence analysis of five genes that encode desmosomal proteins (PKP2, JUP, DSP, DSC2, and DSG2) revealed lower than expected mutation rates, particularly in athletes performing the most exercise. These findings support the notion that intense exercise can induce ARVD/C without an identifiable genetic predisposition.
  • A multi-center study of 108 probands with ARVD/C revealed that 34% were competitive or professional athletes [Marcus et al 2009]. These studies lend further support to the hypothesis that vigorous or sustained athletic activity facilitates the phenotypic expression of the disease due to the repetitive stretch of the thin walled right ventricle with an underlying genetic desmosomal protein abnormality.

Mutations in desmosomal genes have also been identified in 5% of individuals meeting criteria for dilated cardiomyopathy. Although these individuals did not meet criteria for ARVD/C, some did have a history of ventricular arrhythmias and one individual had fibrofatty infiltration on autopsy, leading to the speculation that variants in these desmosomal genes can predispose to heart failure or ventricular arrhythmias [Elliott et al 2010, Bhuiyan & Wilde 2011].

Aquaro et al [2010] studied persons with a prior history of frequent premature ventricular contractions (PVCs) of left bundle branch block morphology and inferior axis. Using cardiac MRI, they assessed functional parameters of the left and right ventricles and then separated the group into those with and those without right ventricular abnormalities. They found that those who had multiple right ventricular abnormalities had a worse outcome (ventricular tachycardia, appropriate ICD shock, sudden cardiac death) than those who did not have right ventricular abnormalities. Further studies are needed to demonstrate the extent to which cardiac MRI can be used to stratify risk.

Compound and digenic heterozygosity of desmosomal genes in ARVD/C. Compound heterozygosity (a mutation in both alleles of the same gene) and digenic heterozygosity (a heterozygous mutation in two different genes) have been seen in autosomal dominant ARVD/C. Many studies have reported on two mutations in ARVD/C-related genes encoding demosomal proteins.

  • It is questioned whether certain heterozygous PKP2 mutations are sufficient to cause disease or if biallelic mutations are necessary [Xu et al 2010]. In an early study of six first-degree relatives of a proband with a PKP2 mutation, two met clinical criteria for ARVD/C and four had either a normal phenotype or mild disease manifestations [Gerull et al 2004]. In a second family, two individuals with a PKP2 mutation died of sudden death at young ages, whereas of five living relatives with the mutation, only one met clinical criteria [Gerull et al 2004]. Subsequent reports have documented families in which relatives with the same pathogenic mutation as the proband do not meet ARVD/C clinical criteria.

    In 42% of individuals with ARVD, Xu et al [2010] identified either compound heterozygosity for two PKP2 mutations or digenic heterozygosity (one heterozygous PKP2 mutation and a second heterozygous mutation in an ARVD/C-related gene encoding a demosomal protein). Xu et al [2010] found a more severe phenotype in those who had compound and digenic heterozygosity when at least one mutation occurred in PKP2. In addition, they speculated that one mutation in PKP2 may not be sufficient to cause disease because some individuals with one PKP2 mutation did not meet revised Task Force criteria [McKenna et al 1994], whereas those in the family with two mutations had ARVD.
  • Bauce et al [2010] found 7.1% of 42 index cases were compound heterozygotes or digenic heterozygotes. When those who were heterozygous for multiple mutations were compared to family members who were heterozygous for a single mutation, the phenotype ranged from no heart disease to severe disease with left ventricular and right ventricular dilatation being more severe in those who were heterozygous for multiple mutations than in those who were heterozygous for a single mutation.
  • Bauce et al [2010] also found that some individuals meeting ARVD diagnostic criteria had two mutations, but that other family members who had a single mutation did not have a clinical diagnosis of ARVD.
  • Barahona-Dussault et al [2010] reported that 43% of their ARVD population with mutations (38% of the study population met the McKenna et al [1994] Task Force criteria) had a mutation in an ARVD-related desmosomal gene, and of these, two (20%) were compound heterozygotes and one (10%) was a digenic heterozygote.
  • Nakajima et al [2012] found that four of seven probands who met Revised Task Force criteria for ARVD/C had two mutations: three were compound heterozygotes and one was a digenic heterozygote [Marcus et al 2010]. The majority of family members of these four probands (who likely would have inherited one of the mutations) remained asymptomatic, suggesting a single variant may not be sufficient to cause clinical manifestations of ARVD.
  • In a study of 65 probands who met ARVD Task force criteria [McKenna et al 1994], Christensen et al [2010b] found mutations in ARVD-associated desmosomal genes in 18, including six with digenic heterozygous mutations, one with compound heterozygous PKP2 mutations, and one with biallelic DSP mutations. The phenotype ranged from severe to mild in compound heterozygotes and digenic heterozygotes.
  • Tan et al [2010] also studied whether compound or digenic heterozygosity confers a more severe disease. Of those individuals with a diagnosis of ARVD based on the 1994 Task Force criteria [McKenna et al 1994], the study found no increase in frequency of compound or digenic heterozygous mutations in a cohort of young (age ≤21 years) individuals with ARVD/C compared to middle age and older affected individuals. Overall, more research is needed on the effects of pathogenic mutations in ARVD/C-related desmosomal genes, and on whether some genes/mutations could have a more severe impact in the compound or digenic heterozygous state versus others that could manifest disease as a single heterozygous mutation.

Genotype-Phenotype Correlations

Currently, insufficient data limit genotype-phenotype correlations. Furthermore, marked variation in phenotype can be observed in individuals from the same family who have the same pathogenic mutation [Gerull et al 2004, Dalal et al 2006].

Mutations in DSP and DSG2 have been associated with more left ventricular involvement than the traditional right ventricular dilatation associated with ARVD/C [Bauce et al 2010].

Penetrance

In the single family with a mutation in DSP reported by Rampazzo et al [2002], penetrance was estimated at 50%. Other estimates of penetrance in kindreds with autosomal dominant ARVD/C are as low as 20%-30% [Sen-Chowdhry et al 2005].

Further studies are needed to establish the penetrance of ARVD/C caused by mutations in other genes.

Genetic variation in ARVD/C-related genes encoding proteins of desmosome structure/function (i.e., DSP, PKP2, DSG2, DSC2, and JUP) that would be considered rare and pathogenic have been identified in 16.2% of healthy Dutch controls compared to 58.3% of Dutch persons meeting 2010 revised Task Force criteria for ARVD/C – an approximately 3.5-fold higher rate in the latter [Kapplinger et al 2011].

However, approximately one in six healthy controls genotyped had a variant in a gene encoding desmosomal proteins that would have been called pathogenic. Kapplinger et al observed that radical mutations (insertions/deletions, splice junction and nonsense mutations) were significantly more prevalent in persons with ARVD/C than in controls (49.9% vs. 0.47% respectively), leading them to propose that this type of genetic variant has a higher likelihood of being associated with ARVD/C pathogenicity. Regarding missense mutations, Kapplinger et al identified three associations with ARVD/C pathogenicity: rare missense mutations identified in a person of northern European origin is more likely pathogenic than one identified in a person of different origin; specific amino-terminal regions of DSP and DSG2 may contain mutation hot spots that have more missense mutations in persons with ARVD/C than controls; and missense mutations that involve a highly conserved residue in PKP2 and DSG2 are more likely pathogenic.

Kapplinger et al do address the concern that variants identified in a control population (with the majority being missense mutations) could be less penetrant in the heterozygous state compared to compound heterozygosity or digenic heterozygosity in those with ARVD/C.

Similarly, Lahtinen et al [2011] screened a Finnish ARVD/C population and general population samples and found mutations in ARVD/C-related genes encoding proteins of desmosome structure/function in one in 200 Finns, including identified founder mutations. Some of those with variants in the general population were actually symptomatic; however, the high mutation prevalence does demonstrate reduced penetrance for many in the general population, as the estimated prevalence of ARVD in the Finnish population is 1:1000 to 1:5000.

Andreasen et al [2013] found that for ARVD/C, 18% of the desmosomal variants previously classified in the literature as pathogenic were found in the Exome Sequencing Project population. This corresponds to a genotype prevalence of 1:5 when the prevalence in the general population is 1:5000, yielding an overrepresentation of genetic variants previously associated with cardiomyopathy in new population-based exome data and leading Andreasen et al to suspect that a high number of these variants may be disease modifiers, or possibly non-pathogenic.

Nomenclature

Arrhythmogenic right ventricular cardiomyopathy (ARVC) has had numerous names including Uhl anomaly and right ventricular dysplasia. Until 1996, ARVC was called arrhythmogenic right ventricular dysplasia (ARVD) [Richardson et al 1996]. Currently the terms ARVC and ARVD are used interchangeably.

Prevalence

The exact prevalence of ARVD/C is unknown but may be estimated at 1:1000 to 1:1250 in the general population [Peters 2006].

The prevalence of ARVD/C is greater in certain regions; in Italy and Greece (Island of Naxos), it can be as high as 0.4%-0.8% [Thiene & Basso 2001].

Differential Diagnosis

ARVD/C and anterior polar cataract (APC). A single family with ARVD/C and subscapular cataract, a rare hereditary form of lens opacity, has been described [Frances et al 1997]. The proband and his sister both had ARVD/C and APC. The gene responsible for APC previously was linked to 14q24qter. Parents of the sibs were second cousins.

DES. Mutations in DES have been identified in individuals with skeletal myopathy (see Myofibrillar Myopathy) or dilated cardiomyopathy with or without cardiac conduction defects, or both myopathy and cardiomyopathy with or without cardiac conduction defects [Goldfarb et al 1998, Dalakas et al 2000]. Families with the phenotype of skeletal myopathy, dilated cardiomyopathy, and ARVD/C per the 1994 ARVD/C diagnostic criteria have been described [van Tintelen et al 2009, Otten et al 2010]. It is unknown at this point whether unique DES mutations cause the ARVD/C phenotype; however, mutations in both the head and tail of DES have been identified as causative of ARVD/C [van Tintelen et al 2009, Otten et al 2010].

Cardiomyopathy. Many forms of cardiomyopathy may mimic aspects of ARVD/C. Cardiomyopathies may arise from genetic, toxic, or immunologic insults. Clinical testing may be useful to distinguish cardiomyopathy from ARVD/C. See Dilated Cardiomyopathy Overview.

Active myocarditis. Inflammation of the myocardium defines acute myocarditis. Myocarditis may arise from viral or other pathogen exposure as well as toxic or immunologic insult. Clinical testing may be useful to distinguish myocarditis from ARVD/C.

Coronary artery disease and myocardial infarction. Coronary artery disease, or atherosclerotic narrowing of the coronary arteries, may lead to acute or chronic ischemic conditions that may mimic aspects of ARVD/C. Clinical testing may be useful to distinguish these from ARVD/C.

Right ventricular outflow tract tachycardia (RVOT) is a clinical arrhythmia condition that is not typically associated with structural heart disease as is seen in ARVD/C. ECG and cardiac imaging may be useful to distinguish these disorders.

Brugada syndrome is characterized by ST segment abnormalities in leads V1-V3 on the ECG and a high risk of ventricular arrhythmias and sudden death. Considerable clinical overlap may be present. One discriminating factor: the right ventricular dilation and fibrofatty infiltration characteristic of ARVD/C is rarely seen in Brugada syndrome.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), the following evaluations are recommended if not performed at the time of diagnosis:

  • ECG
  • Echocardiogram and/or MRI, depending on the expertise of the imaging center
  • Electrophysiology study to assess the risk of ventricular arrhythmias and assess the appropriateness of device insertion (such as an implantable cardioverter defibrillator). A cardiac catheter ablation of tissue causing abnormal rhythms can be performed during the electrophysiology study; however, ablation is typically not effective in individuals with ARVD/C because of the multiple sites of primary ventricular tachycardias.

Treatment of Manifestations

Most affected individuals live a normal lifestyle.

Management of individuals with ARVD/C is complicated by incomplete information on the natural history of the disease as well as variable expressivity of the disease. Management of patients should be individualized and based on the specific results of detailed investigation.

Management is focused on prevention of syncope, cardiac arrest, and sudden death (see Prevention of Primary Manifestations). Recent studies suggest that individuals who present with clinical signs of right heart failure and/or left ventricular dysfunction and have a history of ventricular tachycardia are at high risk and should be treated aggressively [Hulot et al 2004].

Education regarding sudden death risk to affected adults and parents of affected children is an important aspect of management.

Heart transplantation is considered when ARVD/C has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation seems to be rare.

Prevention of Primary Manifestations

Antiarrhythmia medications

  • Beta-blockers
  • Amiodarone
  • Sotalol

Note: In a study of 95 patients with ARVD/C by Marcus et al [2009], neither beta blocker therapy nor sotalol were protective against ventricular arrhythmias. However, amiodarone was associated with lower risk for any clinically relevant arrhythmias. Larger studies are needed to confirm this finding.

Implantable cardioverter-defibrillators (ICDs). ICD placement should be considered in anyone with a clinical diagnosis of ARVD/C.

The ACC/AHA/ESC (American College of Cardiology/American Heart Association Task Force/European Society of Cardiology) guidelines, which are based on experience and previously published reports [Zipes et al 2006], recommend as a Class I indication (i.e., procedure/treatment SHOULD be performed) ICD implantation for prevention of sudden cardiac death in individuals with documented sustained ventricular tachycardia or ventricular fibrillation who are receiving chronic optimal medical therapy and who have reasonable expectation of survival with a good functional status for more than one year. Class II indications (i.e., it is REASONABLE to perform procedure/treatment) for ICD implantation include extensive disease (e.g., left ventricular involvement) or family members with sudden death, or undiagnosed syncope when ventricular fibrillation or ventricular tachycardia cannot be excluded as cause of syncope while the patient was on optimal medical therapy.

Persons who appear to be at the highest risk for a fatal arrhythmia are those who have been resuscitated, are unresponsive to or intolerant of antiarrhythmic therapy, or have first-degree relatives with a history of sudden cardiac arrest.

The appropriate time to place an ICD in an individual at moderate risk for a fatal arrhythmia is not known because ICD efficacy in ARVD/C may be affected by progressive fibrofatty involvement of the right ventricle, which may obscure appropriate sensing of the ICD.

In one study, 44 of 67 persons with ARVD/C with ICDs [Piccini et al 2005] received appropriate* shocks from their ICD for treatment of a sustained ventricular arrhythmia and 16 of 67 received inappropriate shocks for sinus tachycardia, supraventricular tachycardia/atrial fibrillation, or oversensing (i.e., adding an atrial rhythm to the ventricular beat or detecting more waves than are occurring, giving the appearance that the heart is beating faster than it actually is). However, it is difficult to determine whether the ventricular tachycardia was sustained or whether it would have self-corrected without the shock. This study found that appropriate ICD therapies occurred more frequently for persons with definite ARVD/C compared to those with probable ARVD/C. Nonetheless, nearly one third of those with probable ARVD/C received appropriate intervention from the ICD. Therefore, ICD placement should be considered even in those who do not meet 1994 international Task Force ARVD/C diagnostic criteria but have probable ARVD/C (i.e., meeting fewer criteria) and positive findings on electrophysiologic study [Piccini et al 2005].

*Note: 'Appropriate' refers to proper sensing and delivery of defibrillation based on device function.

Corrado et al [2010] studied 106 consecutive individuals with ARVD/C who received an ICD based on arrhythmic risk factors such as syncope, nonsustained ventricular tachycardia, familial sudden death, and inducibility at programmed ventricular stimulation. In follow up at 58 months, 24% had appropriate shock interventions; 16% had shocks for life-threatening ventricular flutter; and 43% with prior syncope experienced appropriate ICD intervention. They also found that syncope, nonsustained ventricular tachycardia, and left ventricular dysfunction were predictors of life-saving ICD intervention. The first appropriate intervention ranged from age 15 to 56 years. None of the 27 who had ICDs implanted because of a history of isolated familial sudden death (i.e., sudden death in an asymptomatic family member who had no prior cardiovascular events) experienced appropriate ICD discharges. Further studies with a larger number of asymptomatic individuals at risk for ARVD/C are needed to determine risks and to refine the recommendations for implantation of an ICD.

Surveillance

Screening for degree of cardiac involvement in persons diagnosed with ARVD/C is essential to ascertain severity and disease progression over time. Screening recommendations:

  • ECG, annually or more frequently depending on symptoms
  • Echocardiogram, annually or more frequently depending on symptoms
  • Holter monitoring
  • Cardiac MRI, frequency depending on symptoms and findings

Agents/Circumstances to Avoid

Individuals with right ventricular dysplasia may be discouraged from vigorous athletic activity including competitive athletics because of the strain caused on the right heart; however, conflicting views exist on restriction of vigorous athletic activity in persons with ARVD/C or those at risk for ARVD/C (See Clinical Description, Natural History for more description).

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to relatives at risk for ARVD/C (even those under age 18 years) if the disease-causing mutation(s) have been identified in an affected family member so that morbidity and mortality can be reduced by early diagnosis and treatment. Predictive testing should be offered in the context of formal genetic counseling.

Note: Consideration should be given to molecular testing of all ARVD/C-related genes versus site-specific testing because of the high rate of digenic heterozygosity (a heterozygous mutation in two different genes) [Barahona-Dussault et al 2010, Wilde 2010, Xu et al 2010]. Studies have not been performed assessing the validity of this consideration.

Guidelines for screening for cardiac involvement in asymptomatic first-degree relatives at risk for ARVD/C [Hershberger et al 2009, Charron et al 2010]:

  • If the family-specific disease-causing mutation has been identified in the asymptomatic at-risk relative, screening for cardiac involvement is recommended yearly between ages ten and 50 years.
  • If genetic testing has not been performed or did not identify a disease-causing mutation in an affected family member, screening for cardiac involvement is recommended for asymptomatic at-risk first-degree relatives every three to five years after age ten years.

Screening for cardiac involvement comprises the following [Hershberger et al 2009, Charron et al 2010]:

  • Medical history with attention to heart failure symptoms, arrhythmia, presyncope and syncope
  • ECG, with consideration of signal averaged electrocardiogram (SAECG)
  • Echocardiogram
  • Holter monitoring
  • Cardiac MRI

At-risk first-degree relatives with any abnormal clinical screening tests for cardiac involvement should be considered for repeat clinical screening in one year [Hershberger et al 2009].

Note: Screening for and diagnosing ARVD/C in children is difficult as early signs of ARVD/C have not been identified by current screening modalities. For example, Bauce et al [2011] studied children who were heterozygous for a mutation in a desmosomal gene (identified by family history and confirmed by genetic testing). In this study, 21 (40%) of 53 heterozygotes met revised ARVD/C diagnostic criteria (age range 11-18 years), four (8%) were borderline and 28 (53%) were unaffected (compared to 20 [38%] of 53 heterozygotes who met the 1994 ARVD/C diagnostic criteria).

  • Of the 16 children under age ten years, none fulfilled 1994 ARVD/C diagnostic criteria.
  • Of the 18 children age 11-14 years, six (33%) were diagnosed with ARVD/C by the 1994 ARVD/C diagnostic criteria and all had ventricular arrhythmias (2 had mild disease, 2 moderate disease, and 2 severe disease).
  • Of the 19 children 14-18 years, eight (42%) were diagnosed with ARVD/C by the 1994 ARVD/C diagnostic criteria. Six (32%) had arrhythmic symptoms; all eight with the diagnosis of ARVD/C had ventricular arrhythmias (4 with sustained VT, 2 with nonsustained VT, 2 with PVCs); and on echocardiogram, one had mild disease, five had moderate disease, and two had severe disease.
  • Overall, 14 individuals were diagnosed with ARVD/C and the majority (39/53, or 74%) did not have any signs or symptoms despite a disease-causing mutation(s) in genes encoding desmosomal proteins.
  • Therefore, continued screening for cardiac involvement despite negative findings is warranted. See Hamilton & Fidler [2009] for a review of screening for ARVD/C in the young.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is usually inherited in an autosomal dominant manner. It can also be inherited in a digenic or autosomal recessive manner.

If the proband has a specific syndrome associated with ARVD/C, such as Naxos disease or Carvajal syndrome, counseling for that autosomal recessive condition is indicated.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Some individuals diagnosed with autosomal dominant ARVD/C have an affected parent.
  • Most people with ARVD/C have a mutation in one ARVD/C-related gene. However, some individuals are identified to have two mutations in the same ARVD/C-related gene. The mutations are usually different and on different alleles (compound heterozygote), but they may be the same mutation on different alleles (homozygous). Rarely, a person has two mutations on the same allele.
    • Typically, one parent has one ARVD/C-causing mutation in the gene and the other parent has a different ARVD/C-causing mutation in the same gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent harbors both disease-causing mutations on the same allele, which would subsequently alter inheritance and risk counseling.
    • The parents may or may not have clinical findings.
  • In addition, a proband with autosomal dominant ARVD/C may have the disorder as the result of a new mutation. The proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include cardiac MRI or echocardiogram, ECG, and molecular genetic testing if the mutation(s) have been identified in the proband.

Note: Although some individuals diagnosed with autosomal dominant ARVD/C have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset or reduced penetrance of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected and/or has a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%. If both parents have a disease-causing mutation, the risk to sibs of inheriting two mutations is 25%, one mutation is 50% and neither mutation is 25%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband may be lower. Variable expressivity and reduced penetrance are common.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with autosomal dominant ARVD/C and one ARVD/C-related mutation has a 50% chance of inheriting the mutation. Each child of an individual with autosomal dominant ARVD/C and two ARVD/C-related mutations (one inherited from each of his/her parents) will inherit one mutation.

Other family members of a proband

Risk to Family Members — Digenic Inheritance

Digenic ARVD/C results from the presence of two mutations: one mutation in one ARVD/C-related gene plus another mutation in a different ARVD/C-related gene.

Parents of a proband

  • Typically, one parent has an ARVD/C-causing mutation in one gene and the other parent has an ARVD/C-causing mutation in a different gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent harbors both disease-causing mutations and is asymptomatic.
  • The parents may or may not have clinical findings.

Sibs of a proband. Assuming that each parent has one mutation, at conception each sib has a 75% chance of inheriting one or two ARVD/C-related mutations (and being at increased risk of developing ARVD/C) and a 25% chance of not inheriting a mutation (and being unaffected).

Offspring of a proband. The risk to offspring of inheriting one or two mutations is 75%.

Other family members of a proband. Each sib of the proband’s parents will have 0, 1, or 2 ARVD/C-related mutations depending on the genetic status of the proband’s parent.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Requests for prenatal testing for conditions which (like ARVD/C) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Heart Association (AHA)
    7272 Greenville Avenue
    Dallas TX 75231
    Phone: 800-242-8721 (toll-free)
    Email: review.personal.info@heart.org
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #20
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937
    Email: sads@sads.org
  • ARVD Patient Registry
    The Johns Hopkins Hospital
    600 North Wolfe Street
    Carnegie 592
    Baltimore MD 21287
    Phone: 410-502-7161
    Fax: 410-502-9148
    Email: ctichnell@jhmi.edu
  • North American ARVD Registry
    1501 North Campbell
    Room 5153
    PO Box 245037
    Tucson AZ 85724-5037
    Phone: 520-626-1416
    Fax: 520-626-4333
    Email: kgear@email.arizona.edu; fmarcus@shc.arizona.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (View All in OMIM)

107970ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 1; ARVD1
125645DESMOCOLLIN 2; DSC2
125647DESMOPLAKIN; DSP
125671DESMOGLEIN 2; DSG2
173325JUNCTION PLAKOGLOBIN; JUP
180902RYANODINE RECEPTOR 2; RYR2
190230TRANSFORMING GROWTH FACTOR, BETA-3; TGFB3
600996ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 2; ARVD2
602086ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 3; ARVD3
602087ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 4; ARVD4
602861PLAKOPHILIN 2; PKP2
604400ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 5; ARVD5
604401ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 6; ARVD6
607450ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8; ARVD8
609040ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 9; ARVD9
609160none found
610193ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; ARVD10
610476ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11; ARVD11
611528ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 12; ARVD12
612048TRANSMEMBRANE PROTEIN 43; TMEM43

Molecular Genetic Pathogenesis

Defects in intercellular connections are one pathogenic mode that leads to arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). This is suggested by mutations in the genes encoding two desmosomal proteins, desmoplakin (DSP) and plakoglobin (JUP), associated with ARVD8/Carvajal syndrome and ARVD12/Naxos disease, respectively.

Altered calcium homeostasis may provide another pathogenic pathway in ARVD/C as suggested by mutations in RYR2 (ARVD2). RYR2 has an important role in calcium release from the sarcoplasmic reticulum and the regulation of excitation-contraction coupling. An impaired intracellular calcium concentration and altered excitation-contraction coupling may predispose to arrhythmias. In addition, impaired intracellular calcium may lead to cellular necrosis, promoting fibrosis and adipose replacement [Tiso et al 2001].

A database of all variants in the genes listed below can be found in the Leiden Open Variation Database or at www.arvcdatabase.info [van der Zwaag et al 2009]. (Links to this database are found in Table A under LSDB.)

RYR2

Gene structure. The gene comprises 105 exons, coding a 565-kd monomer, making it one of the largest human genes. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. In a study by Tiso et al [2001], four missense mutations were identified in four Italian families in highly conserved regions of RYR2. These mutations differ from those found in RYR2 in CPVT. Mutations in RYR2 have also been identified in 'atypical' long QT syndrome [Tester et al 2005].

Normal gene product. The ryanodine receptor 2 regulates calcium flux in the intracellular space and mediates cardiac muscle excitation-contraction coupling [Tiso et al 2001].

Abnormal gene product. RYR2 mutations are thought to result in an uncontrolled calcium leak in the cardiac myocyte, leading to arrhythmia.

DSP

Gene structure. The gene comprises 24 exons, coding 2871 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. At least seven different benign variants have been identified in DSP, primarily missense alterations with one splice site [Barahona-Dussault et al 2010].

Pathogenic allelic variants. In a study by Rampazzo et al [2002], one missense mutation was identified in exon 7 of the proband in an Italian family. At least eight other mutations (nonsense and missense) have been identified in eight different families [Bauce et al 2005, Yang et al 2006].

Normal gene product. Desmoplakin, together with plakoglobin, anchors to desmosomal cadherins, forming an ordered array of non-transmembrane proteins, which then bind to keratin intermediate filaments (IFs) [Kowalczyk et al 1997, Smith & Fuchs 1998, Leung et al 2002]. Desmosomes are major cell-cell junctions, particularly abundant in epidermal cells and in cardiomyocytes [Gallicano et al 1998, Smith & Fuchs 1998]. In addition, desmosomes have been shown to maintain cell integrity as well as participate in cell death and lipid metabolism [Yang et al 2006].

Abnormal gene product. It is speculated that abnormalities in desmoplakin lead to desmosomal instability. Defective desmosomes cannot sustain the constant mechanical stress in contracting cardiomyocytes, resulting in cardiac dysfunction and cell death [Yang et al 2006].

Data from a desmoplakin-deficient mouse model suggest that abnormal desmosomes lead to abnormal β-catenin signaling through Tcf-Lef1 transcription factors resulting in dedifferentiation of myocytes into adipocytes [Garcia-Gras et al 2006].

PKP2

Gene structure. The gene comprises 14 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. At least three different benign variants have been identified in PKP2, all missense alterations [Barahona-Dussault et al 2010].

Pathogenic allelic variants. In a study by Gerull et al [2004], 25 heterozygous mutations were identified in 32 of 120 unrelated probands. Of the 25 PKP2 variants, 12 were insertion-deletion mutations, six were nonsense mutations, four were missense mutations, and three were splice-site mutations. Dalal et al [2006] identified another nine families with PKP2 mutations. Christensen et al [2010a] showed that 15% of Danish persons with ARVD/C had mutations in PKP2. Some previously reported missense mutations in PKP2 (p.Asp26Asn, p.Ser140Phe, p.Val587Ile) were identified at a low frequency in a Danish population of healthy controls, leading them to conclude that missense variants in PKP2 could be disease modifying but not pathogenic [Christensen et al 2010a]. Further characterization of these variants is needed.

Normal gene product. Similar to desmoplakin, plakophilin-2 is a protein of the desmosome and provides structural and functional integrity to adjacent cells.

Abnormal gene product. Abnormalities in plakophilin are thought to perturb intercellular connections and lead to arrhythmia.

DSG2

Gene structure. The gene comprises 15 exons spanning 48.6 kb. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. At least eight different benign variants have been identified in DSG2, all missense alterations [Barahona-Dussault et al 2010].

A previously reported mutation, c.473T>G (p.Val158Gly), was recently reclassified as a nonsynonymous single nucleotide polymorphism (SNP), as it was identified in a control population as well as in unrelated probands with a second confirmed mutation in DSG2 [Bhuiyan et al 2009].

Pathogenic allelic variants. At least 12 mutations have been described. Individuals have been identified as having compound heterozygote mutations [Awad et al 2006, Pilichou et al 2006, Bhuiyan et al 2009]. Some gene variants previously believed to be mutations have been identified in a control population [Milting & Klauke 2008, Posch et al 2008a], as well as being present in some cases of dilated cardiomyopathy [Posch et al 2008b] and, therefore, being possible susceptibility variants rather than pathogenic mutations.

Normal gene product. Desmoglein-2 (DSG2) is a member of the desmoglein family and is an essential component of the desmosome. DSG2 is expressed in myocardium [Awad et al 2006, Pilichou et al 2006].

Abnormal gene product. The effect of an abnormal gene product is unknown at this point; loss of DSG2 results in early embryonic lethality in knockout mice.

DSC2

Gene structure. The gene comprises 17 exons spanning 32 kb. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Four mutations have been described [Heuser et al 2006, Syrris et al 2006]. One individual with a digenic DSG2 mutation has been identified [Bhuiyan et al 2009]. There is a variant that produces a frameshift (p.Ala897LysfsTer4; previously reported as p.Glu896fsTer900) that was originally reported as pathogenic, but it has been identified in six (1.5%) of 400 control chromosomes and is therefore reclassified as a possibly rare variant that could affect phenotypic expression of other mutations that give rise to ARVD/C [DeBortoli et al 2010].

Normal gene product. Desmocollin-2 (DSC2) is ubiquitously expressed in desmosomal tissues and is the only one of three desmocollin isoforms present in cardiac tissue. DSC2 is found in two forms, a and b, produced by alternate splicing of exon 16. Desmocollins bind to desmogleins through their extracellular domains in a Ca2+-dependent manner and their cytoplasmic domains have binding sites for plakoglobin.

Abnormal gene product. Desmocollin mutations resulting in an isoform lacking the last 37 amino acid residues of the carboxyl-terminal domain of DSC2a are unable to bind plakoglobin. It is unknown how the mutations affect desmosome formation, but it is speculated that the result would be impaired desmosomes.

TGFB3

Gene structure. The gene comprises seven exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Two mutations have been described, one in the 5' untranslated region of the gene and the second in the 3' untranslated region of the gene [Beffagna et al 2005].

Normal gene product. TGFB3 encodes for transforming growth factor beta-3, which encodes for a cytokine-stimulating fibrosis and modulates cell adhesion.

Abnormal gene product. It is currently unknown how mutations in TGFB3 cause ARVD/C.

TMEM43

Gene structure. TMEM43 comprises 12 exons coding for 400 amino acids. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. In a study by Merner et al [2008], one putative pathogenic variant, the missense change p.Ser358Leu, was identified in 15 families, all of Newfoundland ancestry. Whether this variant is the causative mutation requires further testing, as it may rather be a benign variant that is in linkage disequilibrium with the causal mutation. A second TMTM43 variant, p.Arg312Trp, seems to be a second founder mutation as it has been found in two Newfoundland probands and their families as well as a family from the United Kingdom; haplotype analysis showed that all share the disease-associated alleles and thus share an ancestral chromosome [Haywood et al 2013].

Normal gene product. TMEM43 codes for a novel transmembrane protein. By bioinformatics analysis, the primary sequence suggests that this protein may be a target of PPARγ. Bioinformatics predicts the protein to be a membrane protein with several post-translational modification sites [Merner et al 2008]. Functional studies are needed.

Abnormal gene product. The pathogenic mechanism of the abnormal gene product is unknown.

JUP

Gene structure. The gene comprises 13 exons, coding for 745 amino acids and an 81.75-kd protein. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. One benign variant (c.2089A>T; Table 2) has been identified as cosegregating with a mutation in desmoplakin. The frequency of the genotypes at position 2089 in the Turkish population is as follows [Uzumcu et al 2006]:

  • Homozygous c.2089T: 0.57
  • Compound heterozygous c.2089A+c.2089T: 0.36
  • Homozygous c.2089A: 0.07

Pathogenic allelic variants. In a study by Asimaki et al [2007], one mutation was identified in the proband of a German family (c.118_119dupGCA) with an autosomal dominant mode of inheritance, although segregation of the mutation was not performed in other affected relatives. A two base pair deletion in JUP (c.2038_2039del) causes Naxos disease, an autosomal recessive cardiocutaneous syndrome. A benign variant (c.2089T>A), is located at position +4 after the acceptor site in exon 3 and thus Uzumcu et al [2006] could not exclude a negative modifier effect on the cardiac phenotype by hypothetic effects on splicing from homozygosity for c.2089A.

Table 2. Selected JUP Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Benignc.2089A>Tp.Met967LeuNM_002230​.2
NP_002221​.1
Pathogenicc.116_118dupGCA
(118_119insGCA)
p.Ser39dup
c.2038_2039del
(PK2157del2)
p.Trp680GlyfsTer11

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. JUP encodes a cytoplasmic protein also known as gamma catenin, which is found in both submembranous plaques of desmosomes and intermediate junctions. The protein, a member of the catenin family, forms distinct complexes with cadherins and desmosomal cadherins. It contains a distinct repeating amino acid motif called the armadillo repeat.

Abnormal gene product. Myocardial biopsy from an affected individual showed that N-cadherin and plakophilin-2 were expressed at control levels; however, plakoglobin, desmoplakin, and connexin 43 were significantly reduced at the intercalated discs.

In vivo models suggest that the mutation affects the structure and distribution of mechanical and electrical cell junctions and could interfere with regulatory mechanisms mediated by Wnt-signaling pathways [Asimaki et al 2007].

References

Published Guidelines/Consensus Statements

  1. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, HAuer R, Nava A, Picard MH, Protonotarios N, Safitz JE, Yoeger Sanborn DM, Steinberg JS, Tandri H, Theine G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Available online. 2010. Accessed 12-31-13. [PMC free article: PMC2860804] [PubMed: 20172911]

Literature Cited

  1. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE. HRS/EHRA Expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8:1308–39. [PubMed: 21787999]
  2. Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T. A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol. 2003;42:319–27. [PubMed: 12875771]
  3. Aquaro GD, Pingitore A, Strata E, Di Bella G, Molinaro S, Lombardi M. Cardiac magnetic resonance predicts outcome in patients with premature ventricular complexes of left bundle branch block morphology. J Am Coll Cardiol. 2010;56:1235–43. [PubMed: 20883930]
  4. Asimaki A, Syrris P, Wichter T, Matthias P, Saffitz JE, McKenna WJ. A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2007;81:964–73. [PMC free article: PMC2265660] [PubMed: 17924338]
  5. Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE. A new diagnostic test for arrhythmogenic right ventricular cardiomyopathy. N Engl J Med. 2009;360:1075–84. [PubMed: 19279339]
  6. Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, Tucker A, Russell SD, Bluemke DA, Dietz HC, Calkins H, Judge DP. DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet. 2006;79:136–42. [PMC free article: PMC1474134] [PubMed: 16773573]
  7. Barahona-Dussault C, Benito B, Campuzano O, Iglesias A, Leung TL, Robb L, Talajic M, Brugada R. Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Clin Genet. 2010;77:37–48. [PubMed: 19863551]
  8. Bauce B, Basso C, Rampazzo A, Beffagna G, Daliento L, Frigo G, Malacrida S, Settimo L, Danieli G, Thiene G, Nava A. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J. 2005;26:1666–75. [PubMed: 15941723]
  9. Bauce B, Nava A, Beffagna G, Basso C, Lorenzon A, Smaniotto G, De Bortoli M, Rigato I, Mazzotti E, Steriotis A, Marra MP, Towbin JA, Thiene G, Danieli GA, Rampazzo A. Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm. 2010;7:22–9. [PubMed: 20129281]
  10. Bauce B, Rampazzo A, Basso C, Mazzotti E, Rogato I, Steriotis A, Beffagna G, Lorenzon A, DeBortoli M, Pilicou K, Marra MP, Corbetti F, Daliento L, Iliceto S, Corrado D, Thiene G, Nava A. Clinical phenotype and diagnosis of arrhythmogenic right ventricular cardiomyopathy in pediatric patients carrying desmosomal gene mutations. Heart Rhythm. 2011;8:1686–95. [PMC free article: PMC3205183] [PubMed: 21723241]
  11. Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, Bauce B, Carraro G, Thiene G, Towbin JA, Danieli GA, Rampazzo A. Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res. 2005;65:366–73. [PubMed: 15639475]
  12. Bhuiyan ZA, Jongbloed JDH, van der Smagt J, Lombardi PM, Wiesfeld ACP, Nelen M, Schouten M, Jongbloed R, Cox MGPJ, van Wolferen M, Rodriguez LM, van Gelder IC, Bikker H, Suurmeijer AJH, van den Berg M, Mannens MMAM, Hauer RNW, Wilde AAM, van Tintelen P. Desmoglein-2 and desmocollin-2 mutations in Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy patients: results from a multicenter study. Circ Cardiovasc Genet. 2009;2:418–27. [PubMed: 20031616]
  13. Bhuiyan ZA, Wilde AA. Desmosomal mutations across the fence. Heart Rhythm. 2011;8:1222–3. [PubMed: 21459163]
  14. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol. 1998;39:418–21. [PubMed: 9738775]
  15. Chalabreysse L, Senni F, Bruyere P, Aime B, Ollagnier C, Bozio A, Bouvagnet P. A new hypo/oligodontia syndrome: Carvajal/Naxos syndrome secondary to desmoplakin-dominant mutations. J Dent Res. 2011;90:58–64. [PubMed: 20940358]
  16. Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P, Helio T, Keren A, McKenna WJ, Monserrat L, Pankuweit S, Perrot A, Rapezzi C, Ristic A, Seggewiss H, van Langen I, Tavazzi L. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31:2715–28. [PubMed: 20823110]
  17. Christensen AH, Benn M, Bundgaard H, Tybjaerg-Hansen A, Haunso S, Svendsen JH. Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy. J Med Genet. 2010b;47:736–44. [PubMed: 20864495]
  18. Christensen AH, Benn M, Tybjaerg-Hansen A, Haunso S, Svendsen JH. Missense variants in plakophilin-2 in arrhythmogenic right ventricular cardiomyopathy patients-disease causing or innocent bystanders. Cardiology. 2010a;115:148–54. [PubMed: 19955750]
  19. Corrado D, Basso C, Leoni L, Tokajuk B, Bauce B, Frigo G, Tarantini G, Napodano M, Turrini P, Ramondo A, Daliento L, Nava A, Buja G, Iliceto S, Thiene G. Three-dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2005;111:3042–50. [PubMed: 15939822]
  20. Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. N Engl J Med. 1998;339:364–9. [PubMed: 9691102]
  21. Corrado D, Calkins H, Link MS, Leoru L, Favale S, Bevilacqua M, Basso C, Ward D, Boriani G, Ricci R, Piccini JP, Dalal D, Santini M, Buja G, Iliceto S, Estes NAM, Wichter T, McKenna WJ, Thiene G, Marcus FI. Prophylactic implatable defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation or sustained ventricular tachycardia. Circulation. 2010;122:1144–52. [PubMed: 20823389]
  22. Coumel P, Fidelle J, Lucet V, Attuel P, Bouvrain Y. Catecholaminergic-induced severe ventricular arrhythmias with Adams-Stokes syndrome in children: report of four cases. Br Heart J. 1978;40 Suppl:28–37.
  23. Dalakas M, Park KY, Semino-Mora C, Lee HS, Sivakumar K, Goldfarb LG. Desmin myopathy, a skeletalk myopathy with cardiomyopathy caused by mutations in the desmin gene. N Engl J Med. 2000;342:770–80. [PubMed: 10717012]
  24. Dalal D, James C, Devanagondi R, Tichnell C, Tucker A, Prakasa K, Spevak PJ, Bluemke DA, Abraham T, Russell SD, Calkins H, Judge DP. Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2006;48:1416–24. [PubMed: 17010805]
  25. Dalal D, Nasir K, Bomma C, Prakasa K, Tandri H, Piccini J, Roguin A, Tichnell C, James C, Russell SD, Judge DP, Abraham T, Spevak PJ, Bluemke DA, Calkins H. Arrhythmogenic right ventricular dysplasia: a United States experience. Circulation. 2005;112:3823–32. [PubMed: 16344387]
  26. De Bortoli M, Beffagna G, Bauce B, Lorenzon A, Smaniotto G, Rigato I, Calore M, Mura IEAL, Basso C, Thiene G, Lanfranchi G, Danieli GA, Nava A, Rampazzo A. The p.A897KfsX4 frameshift variation in desmocollin-2 is not a causative mutation in arrhythmogenic right ventricular cardiomyopathy. Eur J Hum Genet. 2010;18:776–82. [PMC free article: PMC2987370] [PubMed: 20197793]
  27. Elliott P, O’Mahony C, Syrris P, Evans A, Sorensen CR, Sheppart MN, Carr-White G, Pantazis A, McKenna WJ. Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy. Circ Cardiovasc Genet. 2010;3:314–22. [PubMed: 20716751]
  28. Firoozi S, Sharma S, McKenna WJ. Risk of competitive sport in young athletes with heart disease. Heart. 2003;89:710–4. [PMC free article: PMC1767726] [PubMed: 12807837]
  29. Fogel MA, Weinberg PM, Harris M, Rhodes L. Usefulness of magnetic resonance imaging for the diagnosis of right ventricular dysplasia in children. Am J Cardiol. 2006;97:1232–7. [PubMed: 16616032]
  30. Fontaine G, Fontaliran F, Frank R. Arrhythmogenic right ventricular cardiomyopathies: clinical forms and main differential diagnoses. Circulation. 1998;97:1532–5. [PubMed: 9593556]
  31. Frances R, Rodriguez Benitez AM, Cohen DR. Arrhythmogenic right ventricular dysplasia and anterior polar cataract. Am J Med Genet. 1997;73:125–6. [PubMed: 9409860]
  32. Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V, Degenstein L, Fuchs E. Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage. J Cell Biol. 1998;143:2009–22. [PMC free article: PMC2175222] [PubMed: 9864371]
  33. Garcia-Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, Marian AJ. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest. 2006;116:2012–21. [PMC free article: PMC1483165] [PubMed: 16823493]
  34. Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004;36:1162–4. [PubMed: 15489853]
  35. Goldfarb LG, Park KY, Cervanakova L, Gorokhova S, Lee HS, Vasconcelos O, Nagle JW, Semino-Mora C, Sivakumar K, Dalakas MC. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet. 1998;19:402–3. [PubMed: 9697706]
  36. Hamid MS, Norman M, Quraishi A, Firoozi S, Thaman R, Gimeno JR, Sachdev B, Rowland E, Elliott PM, McKenna WJ. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol. 2002;40:1445–50. [PubMed: 12392835]
  37. Hamilton RM, Fidler L. Right ventricular cardiomyopathy in the young: an emerging challenge. Heart Rhythm. 2009;6:571–5. [PubMed: 19324321]
  38. Haywood AFM, Merner ND, Hodgkinson KA, Houston J, Syrris P, Booth V, Connors S, Pantazis A, Quarta G, Elliott P, McKenna W, Young TL. Recurrent missense mutations in TMTM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada. Eur Heart J. 2013;34:1002–11. [PubMed: 23161701]
  39. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MRG, Towbin JA. Genetic evaluation of cardiomyopathy-A heart failure society of America practice guideline. J Cardiac Fail. 2009;15:83–97. [PubMed: 19254666]
  40. Heuser A, Plovie ER, Ellinor PT, Grossmann KS, Shin JT, Wichter T, Basson CT, Lerman BB, Sasse-Klaassen S, Thierfelder L, MacRae CA, Gerull B. Mutant desmocollin-2 causes arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2006;79:1081–8. [PMC free article: PMC1698714] [PubMed: 17186466]
  41. Hodgkinson KA, Parfrey PS, Bassett AS, Kupprion C, Drenckhahn J, Norman MW, Thierfelder L, Stuckless SN, Dicks EL, McKenna WJ, Connors SP. The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol. 2005;45:400–8. [PMC free article: PMC3133766] [PubMed: 15680719]
  42. Horimoto M, Akino M, Takenaka T, Igarashi K, Inoue H, Kawakami Y. Evolution of left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy. Cardiology. 2000;93:197–200. [PubMed: 10965092]
  43. Hulot JS, Jouven X, Empana JP, Frank R, Fontaine G. Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation. 2004;110:1879–84. [PubMed: 15451782]
  44. Jacob KA, Noorman M, Cox MGPJ, Groeneweg JA, Hauer RNW, van der Heyden MAG. Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy. Neth Heart J. 2012;20:234–9. [PMC free article: PMC3346879] [PubMed: 22527912]
  45. Jain A, Shehta ML, Stuber M, Berkowitz SJ, Calkins H, Lima JAC, Bluemke DA, Tandri H. Prevalence of left ventricular regional dysfunction in arrhythmogenic right ventricular dysplasia: a tagged MRI study. Circ Cardiovasc Imaging. 2010;3:290–7. [PMC free article: PMC3036009] [PubMed: 20197508]
  46. Kapplinger JD, Landstrom AP, Salisbury BA, Callis TE, Pollevick GD, Tester DJ, Cox MGPJ, Bhuiyan Z, Bikker H, Wiesfeld ACP, Hauer RNW, van Tintelen JP, Jongbloed JDH, Calkins H, Judge DP, Wilde AMM, Ackerman MJ. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background noise. JACC. 2011;57:2317–27. [PubMed: 21636032]
  47. Kowalczyk AP, Bornslaeger EA, Borgwardt JE, Palka HL, Dhaliwal AS, Corcoran CM, Denning MF, Green KJ. The amino-terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin-plakoglobin complexes. J Cell Biol. 1997;139:773–84. [PMC free article: PMC2141713] [PubMed: 9348293]
  48. La Gerche A, Robberecht C, Kuiperi C, Nuyens D, Willems R, de Ravel T, Matthijs G, Heidbüchel H. Lower than expected desmosomal gene mutation prevalence in endurance athletes with complex ventricular arrhythmias of right ventricular origin. Heart. 2010;96:1268–74. [PubMed: 20525856]
  49. Lahtinen AM, Lehtonen E, Marjamaa A, Kaartinen M, Helio T, Porthan K, Oikarinen L, Toivonen L, Swan H, Jula A, Peltonen L, Palotie A, Salomaa V, Kontula K. Population prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm. 2011;8:1214–21. [PubMed: 21397041]
  50. Laitinen PJ, Brown KM, Piippo K, Swan H, Devaney JM, Brahmbhatt B, Donarum EA, Marino M, Tiso N, Viitasalo M, Toivonen L, Stephan DA, Kontula K. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001;103:485–90. [PubMed: 11157710]
  51. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation. 1995;91:1512–9. [PubMed: 7867192]
  52. Lemola K, Brunckhorst C, Helfenstein U, Oechslin E, Jenni R, Duru F. Predictors of adverse outcome in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy: long term experience of a tertiary care centre. Heart. 2005;91:1167–72. [PMC free article: PMC1769099] [PubMed: 16103549]
  53. Leung CL, Green KJ, Liem RK. Plakins: a family of versatile cytolinker proteins. Trends Cell Biol. 2002;12:37–45. [PubMed: 11854008]
  54. Li D, Ahmad F, Gardner MJ, Weilbaecher D, Hill R, Karibe A, Gonzalez O, Tapscott T, Sharratt GP, Bachinski LL, Roberts R. The locus of a novel gene responsible for arrhythmogenic right-ventricular dysplasia characterized by early onset and high penetrance maps to chromosome 10p12-p14. Am J Hum Genet. 2000;66:148–56. [PMC free article: PMC1288320] [PubMed: 10631146]
  55. Limura I, Bauce B, Nava A, Fanciulli M, Vazza G, Mazzotti E, Rigato I, DeBortoli M, Beffagna G, Lorenzon A, Calore M, Dazzo E, Nobile C, Mostacciuolo L, Corrado D, Basso C, Daliento L, Ghiene G, Rampazzo A. Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy. Eur J Hum Genet. 2013;(March):13. [PMC free article: PMC3798844] [PubMed: 23486541]
  56. Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation. 1982;65:384–98. [PubMed: 7053899]
  57. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Safitz JE, YoegerSanborn DM, Steinberg JS, Tandri H, Theine G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121:1533–41. [PMC free article: PMC2860804] [PubMed: 20172911]
  58. Marcus GM, Glidden DV, Polonsky B, Zareba W, Smith LM, Cannom DS, Estes NAM, Marcus F, Scheinman MM. Efficacy of antiarrhythmic drugs in arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2009;54:609–615. [PMC free article: PMC2748738] [PubMed: 19660690]
  59. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the united states, 1980, 2006. Circulation. 2009;119:1085–92. [PubMed: 19221222]
  60. Matolweni LO, Bardien S, Rebello G, Oppon E, Munclinger M, Ramesar R, Watkins H, Mayosi BM. Arrhythmogenic right ventricular cardiomyopathy type 6 (ARVC6): support for the locus assignment, narrowing of the critical region and mutation screening of three candidate genes. BMC. 2006;7:29. [PMC free article: PMC1444927] [PubMed: 16569242]
  61. McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, Camerini F. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Task Force of the Working Group Myocardial and Pericardial Disease of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International Society and Federation of Cardiology. Br Heart J. 1994;71:215–8. [PMC free article: PMC483655] [PubMed: 8142187]
  62. McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, Norman M, Baboonian C, Jeffery S, McKenna WJ. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000;355:2119–24. [PubMed: 10902626]
  63. Melberg A, Oldfors A, Blomstrom-Lundqvist C, Stalberg E, Carlsson B, Larsson E, Lidell C, Eeg-Olofsson KE, Wikstrom G, Henriksson KG, Dahl N. Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy linked to chromosome 10q. Ann Neurol. 1999;46:684–92. [PubMed: 10970245]
  64. Merner ND, Hodgkinson KA, Haywood AFM, Connors S, French VM, Drenckhahn JD, Kupprion C, Ramadanova K, Thierfelder L, McKenna W, Gallagher B, Morris-Larkin L, Bassett AS, Parfrey PS, Young TL. Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:809–21. [PMC free article: PMC2427209] [PubMed: 18313022]
  65. Milting H, Klauke B. Molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008;5:E1. [PubMed: 18813333]
  66. Murphy DT, Shine SC, Cradock A, Galvin JM, Keelan ET, Murray JG. Cardiac MRI in arrhythmogenic right ventricular cardiomyopathy. AJR. 2010;194:W299–W306. [PubMed: 20308474]
  67. Nakajima T, Kaneko Y, Irie T, Takahashi R, Kato T, Iijima T, Iso T. Compound and digenic heterozygosity in desmosomal genes as a cause of arrhythmogenic right ventricular cardiomyopathy in Japanese patients. Circ J. 2012;76:737–43. [PubMed: 22214898]
  68. Nava A, Bauce B, Basso C, Muriago M, Rampazzo A, Villanova C, Daliento L, Buja G, Corrado D, Danieli GA, Thiene G. Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2000;36:2226–33. [PubMed: 11127465]
  69. Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE, Whittock N, Leigh IM, Stevens HP, Kelsell DP. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet. 2000;9:2761–6. [PubMed: 11063735]
  70. Otten E, Asimaki A, Maass A, van Langen IM, van der Wal A, de Jonge N, van den Berg MP, Saffitz JE, Wilde AAM, Jongbloed JDH, van Tintelen JP. Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks. Heart Rhythm. 2010;7:1058–1064. [PubMed: 20423733]
  71. Peters S. Advances in the diagnostic management of arrhythmogenic right ventricular dysplasia-cardiomyopathy. Int J Cardiol. 2006;113:4–11. [PubMed: 16737750]
  72. Piccini JP, Dalal D, Roguin A, Bomma C, Cheng A, Prakasa K, Dong J, Tichnell C, James C, Russell S, Crosson J, Berger RD, Marine JE, Tomaselli G, Calkins H. Predictors of appropriate implantable defibrillator therapies in patients with arrhythmogenic right ventricular dysplasia. Heart Rhythm. 2005;2:1188–94. [PubMed: 16253908]
  73. Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, Frigo G, Vettori A, Valente M, Towbin J, Thiene G, Danieli GA, Rampazzo A. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation. 2006;113:1171–9. [PubMed: 16505173]
  74. Posch MG, Posch MJ, Geier C, Erdmann B, Mueller W, Richter A, Ruppert V, Pankuweit S, Maisch B, Perrot A, Buttgereit J, Dietz R, Haverkamp W, Ozcelik C. A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy. Mol Genet Metab. 2008a;95:74–80. [PubMed: 18678517]
  75. Posch MG, Posch MJ, Perrot A, Dietz R, Ozcelik C. Variations in DSG2: V56M, V158G and V920G are not pathogenic for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008b;5:E1. [PubMed: 19039334]
  76. Prakasa KR, Dalal D, Wang J, Bomma C, Tandri H, Dong J, James C, Tichnell C, Russell SD, Spevak P, Corretti M, Bluemke DA, Calkins H, Abraham TP. Feasibility and variability of three dimensional echocardiography in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Cardiol. 2006;97:703–9. [PubMed: 16490442]
  77. Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli G A. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2000;102:r49–r53. [PubMed: 11208676]
  78. Protonotarios N, Tsatsopoulou A, Anastasakis A, Sevdalis E, McKoy G, Stratos K, Gatzoulis K, Tentolouris K, Spiliopoulou C, Panagiotakos D, McKenna W, Toutouzas P. Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin. J Am Coll Cardiol. 2001;38:1477–84. [PubMed: 11691526]
  79. Quarta G, Muir A, Pantazis A, Syrris P, Gehmlich K, Garcia-Pavia P, Sen-Chowdhry S, Elliott PM, McKenna WJ. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123:2701–9. [PubMed: 21606390]
  80. Quarta G, Ward D, Tome Esteban MT, Pantazis A, Elliott PM, Volpe M, Autore C, McKenna WJ. Dynamic electrocardiographic changes in patients with arrhythmogenic right ventricular cardiomyopathy. Heart. 2010;96:516–22. [PubMed: 20350987]
  81. Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, Zimbello R, Simionati B, Basso C, Thiene G, Towbin JA, Danieli GA. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002;71:1200–6. [PMC free article: PMC385098] [PubMed: 12373648]
  82. Rampazzo A, Nava A, Miorin M, Fonderico P, Pope B, Tiso N, Livolsi B, Zimbello R, Thiene G, Danieli GA. ARVD4, a new locus for arrhythmogenic right ventricular cardiomyopathy, maps to chromosome 2 long arm. Genomics. 1997;45:259–63. [PubMed: 9344647]
  83. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O'Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996;93:841–2. [PubMed: 8598070]
  84. Roberts JD, Herkert JC, Rutberg J, Nikkel SM, Wiesfeld ACP, Dooijes D, Gow RM, van Tintelen JP, Gollob MH. Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy. Clin Genet. 2013;83:452–6. [PubMed: 22889254]
  85. Sen-Chowdhry S, Prasad SK, Syrris P, Wage R, Ward D, Merrifield R, Smith GC, Firmin DN, Pennell DJ, McKenna WJ. Cardiovascular magnetic resonance in arrhythmogenic right ventricular cardiomyopathy revisited: comparison with task force criteria and genotype. J Am Coll Cardiol. 2006;48:2132–40. [PubMed: 17113003]
  86. Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol. 2005;16:927–35. [PubMed: 16101641]
  87. Sen-Chowdhry S, Syrris P, Ward D, Asimaki A, Sevdalis E, McKenna WJ. Clinical and genetic characterization of families with arrhythmogenic right ventricular dysplasia/cardiomyopathy provides novel insights into patterns of disease expression. Circulation. 2007;115:1710–20. [PubMed: 17372169]
  88. Severini GM, Krajinovic M, Pinamonti B, Sinagra G, Fioretti P, Brunazzi MC, Falaschi A, Camerini F, Giacca M, Mestroni L. A new locus for arrhythmogenic right ventricular dysplasia on the long arm of chromosome 14. Genomics. 1996;31:193–200. [PubMed: 8824801]
  89. Simpson MA, Mansour S, Ahnood D, Kalidas K, Patton MA, McKenna WJ, Behr ER, Crosby AH. Homozygous mutation of desmocollin-2 in arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair. Cardiology. 2009;113:28–34. [PubMed: 18957847]
  90. Smith EA, Fuchs E. Defining the interactions between intermediate filaments and desmosomes. J Cell Biol. 1998;141:1229–41. [PMC free article: PMC2137181] [PubMed: 9606214]
  91. Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, McKenna WJ. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet. 2006;79:978–84. [PMC free article: PMC1698574] [PubMed: 17033975]
  92. Tabib A, Loire R, Chalabreysse L, Meyronnet D, Miras A, Malicier D, Thivolet F, Chevalier P, Bouvagnet P. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation. 2003;108:3000–5. [PubMed: 14662701]
  93. Teske AJ, De Boeck BW, Melman PG, Sieswerda GT, Doevendans PA, Cramer MJ. Echocardiographic quantification of myocardial function using tissue deformation imaging, a guide to image acquisition and analysis using tissue Doppler and speckle tracking. Cardiovasc Ultrasound. 2007;30:5–27. [PMC free article: PMC2000459] [PubMed: 17760964]
  94. Tester DJ, Kopplin LJ, Will ML, Ackerman MJ. Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart Rhythm. 2005;2:1099–105. [PubMed: 16188589]
  95. Thiene G, Basso C. Arrhythmogenic right ventricular cardiomyopathy: An update. Cardiovasc Pathol. 2001;10:109–17. [PubMed: 11485854]
  96. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med. 1988;318:129–33. [PubMed: 3336399]
  97. Tiso N, Stephan DA, Nava A, Bagattin A, Devaney JM, Stanchi F, Larderet G, Brahmbhatt B, Brown K, Bauce B, Muriago M, Basso C, Thiene G, Danieli GA, Rampazzo A. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001;10:189–94. [PubMed: 11159936]
  98. Uzumcu A, Norgett EE, Dindar A, Uyguner O, Nisli K, Kayserilli H. Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome. J Med Genet. 2006;43:e5. [PMC free article: PMC2564645] [PubMed: 16467215]
  99. van der Zwaag PA, Jongbloed JDH, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H, Hofstra RMW, van Tintelen P. A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy. Hum Mutat. 2009;30:1278–83. [PubMed: 19569224]
  100. van Tintelen JP, Hauer RNW. New test for arrhythmogenic right ventricular cardiomyopathy. Nature. 2009;6:450–1. [PubMed: 19554004]
  101. van Tintelen JP, van Gelder IC, Asimaki A, Suurmeijer AJH, Wiesfeld ACP, Jongbloed JDH, van den Wijngaard A, Kuks JBM, van Spaendonck-Zwarts KY, Notermans N, Boven L, van den Huevel F, Veenstra-Knol HE, Saffitz JE, Hofstra RMW, van den Berg MP. Severe cardiac phenotype with right ventricular predominance in a large cohort of patients with a single missense mutation in the DES gene. Heart Rhythm. 2009;6:1574–83. [PubMed: 19879535]
  102. Whittock NV, Wan H, Morley SM, Garzon MC, Kristal K, Hyde P, McLean WH, Pulkkinen L, Uitto J, Christiano AM, Eady RA, McGrath JA. Compound heterozygosity for nonsense and missense mutations in desmoplakin underlies skin fragility/wooly hair syndrome. J Invest Dermatol. 2002;118:232–48. [PubMed: 11841538]
  103. Wilde AAM. Long QT syndrome: A double hit hurts more. Heart Rhythm. 2010;7:11419–1420. [PubMed: 20601150]
  104. Xu T, Yang Z, Vatta M, Rampazzo A, Beffagna G, Pillichou K, Scherer SE, Saffitz J, Kravitz J, Zareba W, Danieli GA, Lorenzon A, Nava A, Bauce B, Thiene G, Basso C, Calkins H, Gear K, Marcus F, Towbin JA. Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2010;55:587–97. [PMC free article: PMC2852685] [PubMed: 20152563]
  105. Yang Z, Bowles NE, Scherer SE, Taylor MD, Kearney DL, Ge S, Nadvoretskiy VV, DeFreitas G, Carabello B, Brandon LI, Godsel LM, Green KJ, Saffitz JE, Li H, Danieli GA, Calkins H, Marcus F, Towbin JA. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Res. 2006;99:646–55. [PubMed: 16917092]
  106. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden DM, Silka MJ, Tracy C, Blanc JJ, Budaj A, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL, Smith SC, Jacobs AK, Adams CD, Antman EM, Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B. American College of Cardiology/American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association and the Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death--executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J. 2006;27:2099–140. [PubMed: 16923744]

Suggested Reading

  1. Calkins H. Arrhythmogenic right-ventricular dysplasia/cardiomyopathy. Curr Opin Cardiol. 2006;21:55–63. [PubMed: 16355031]
  2. Capulzini L, Brugda P, Brugada J, Brugada R. Arrhythmia and Right Heart Disease: From Genetic Basis to Clinical Practice. Rev Esp Cardiol. 2010;63:963–83. [PubMed: 20738941]
  3. Delmar M, McKenna WJ. The cardiac desmosome and arrhythmogenic cardiomyopathies: from gene to disease. Circ Res. 2010;107:700–14. [PubMed: 20847325]
  4. Frances RJ. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. A review and update. Int J Cardiol. 2006;110:279–87. [PubMed: 16099519]
  5. Kies P, Bootsma M, Bax J, Schalij MJ, van der Wall EE. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: screening, diagnosis, and treatment. Heart Rhythm. 2006;3:225–34. [PubMed: 16443541]
  6. Moric-Janiszewska E, Markiewicz-Loskot G. Review on the genetics of arrhythmogenic right ventricular dysplasia. Europace. 2007;9:259–66. [PubMed: 17363426]
  7. Sen-Chowdhry S, Morgan RD, Chambers JC, McKenna WJ. Arrhythmogenic cardiomyopathy: etiology, diagnosis and treatment. Annu Rev Med. 2010;61:233–53. [PubMed: 20059337]

Chapter Notes

Acknowledgments

This work was supported by the Doris Duke Charitable Foundation.

Revision History

  • 9 January 2014 (me) Comprehensive update posted live
  • 13 October 2009 (cd) Revision: sequence analysis available clinically for TGFB3 mutations
  • 15 December 2008 (cd) Revision: clinical testing for JUP mutations (ARVD12); prenatal testing for ARVD/C 5 (TMEM43)
  • 10 July 2008 (cd) Revision: sequence analysis available clinically for TMEM43 mutations (ARVD5)
  • 12 December 2007 (me) Comprehensive update posted to live Web site
  • 5 April 2006 (cd) Revision: Clinical testing for DSP and PKP2 available; prenatal diagnosis for PKP2 available
  • 18 April 2005 (me) Review posted to live Web site
  • 6 July 2004 (em) Original submission
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