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Arrhythmogenic Right Ventricular Cardiomyopathy

Synonyms: ARVC, ARVD

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

Author Information

Initial Posting: ; Last Update: May 25, 2017.

Summary

Clinical characteristics.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – 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, and 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 ARVC is made using a combination of noninvasive and invasive tests to evaluate cardiac structure and rhythm. The common genetic causes known to be associated with ARVC are: DSC2, DSG2, DSP, JUP, PKP2, and TMEM43. Less common genetic causes include CTNNA3, DES, LMNA, PLN, RYR2, TGFB3, and TTN. A subset of these 13 genes encode components of the desmosome.

Management.

Treatment of manifestations: Management is individualized and focused on prevention of syncope, cardiac arrest, and sudden death through use of antiarrhythmic medication and an implantable cardioverter-defibrillator. Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure, although severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation appears to be rare.

Agents/circumstances to avoid: Regular, vigorous athletic activity including competitive athletics should be discouraged because of the strain caused on the right heart and its promotion of ARVC and associated arrhythmias.

Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives in families in which the pathogenic variant is known; those with the family-specific pathogenic variant 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 pathogenic variant in an affected family member, clinical screening for cardiac involvement is recommended for asymptomatic at-risk first-degree relatives every three to five years after age ten years.

Genetic counseling.

ARVC is typically inherited in an autosomal dominant manner. A proband with autosomal dominant ARVC may have the disorder as a result of a de novo pathogenic variant. The proportion of cases caused by a de novo variant is unknown. Each child of an individual with autosomal dominant ARVC has a 50% chance of inheriting the pathogenic variant. ARVC may also be inherited in a digenic manner (i.e., a single allele of two different genes has a pathogenic variant). Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) have been identified in the family.

Diagnosis

ARVC is a primary cardiomyopathy that is most commonly diagnosed after an individual presents with arrhythmia findings. Diagnostic criteria were initially proposed by an international task force [McKenna et al 1994], and were revised by Marcus et al [2010]. Diagnostic criteria rely on a combination of ECG and signal averaged ECGs, imaging studies that include 2D echocardiography, cardiac MRI or RV angiography, and arrhythmia presence documented by telemetric monitoring, genetic testing, and family history.

Suggestive Findings

Arrhythmogenic right ventricular cardiomyopathy (ARVC) should be suspected in individuals with any of the following findings:

  • Syncope
  • Palpitations
  • Sudden cardiac death
  • Abnormal ECG
  • Abnormal right ventricle seen through cardiac imaging

Diagnostic criteria for ARVC, 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 ARVC based on the number of major and/or minor diagnostic criteria present (see Establishing the Diagnosis).

Imaging Findings: Global and/or Regional Cardiac Dysfunction and Structural Alterations

Major

  • By 2D echo
    • Regional right ventricular (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 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 BSA ≥16 to <19 mm/m2
      • PSAX RVOT ≥32 to <36 mm; corrected for 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%

Endomyocardial Biopsy or Autopsy Findings

Major. Residual myocytes lower than 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

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

ECG Findings

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 ≥120 ms)
  • Minor
    • Inverted T waves in leads V1 and V2 in individuals age >14 years (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 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

Establishing the Diagnosis

The diagnosis of ARVC is established in a proband with the following findings from different categories (see Suggestive Findings):

• Two major criteria; OR

• One major AND two minor criteria; OR

• Four minor criteria

In the task force criteria, a heterozygous pathogenic variant in one of the genes listed in Table 1a or Table 1b detected by molecular genetic testing is considered a major criterion.

Molecular genetic testing approaches can include use of a multigene panel and more comprehensive genomic testing:

  • A multigene panel that includes DSC2, DSG2, DSP, JUP, PKP2, and TMEM43 and other genes of interest (see Differential Diagnosis) is recommended as the primary test for the proband. Other genes to include on the panel are CTNNA3, DES, LMNA, PLN, RYR2, TGFB3, and TTN. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Alternatively, broader cardiomyopathy gene panels can be considered as first-line testing since there is phenotypic and genotypic overlap with dilated, hypertrophic, and left ventricular noncompaction cardiomyopathies. A broader cardiomyopathy panel can also be considered as an intermediate test prior to using comprehensive genomic testing. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Note: With the expansion of gene panel testing for ARVC, individuals with two pathogenic variants may be found (digenic/biallelic inheritance). The estimate of digenic/biallelic inheritance varies from 4-47% [Xu et al 2010, Bao et al 2013, Rigato et al 2013, Bhonsale et al 2015, Groeneweg et al 2015]. In most studies, digenic/biallelic carriers have a more severe arrhythmia phenotype. See Genotype/Phenotype Correlations.

Table 1a.

Molecular Genetic Testing Used in Arrhythmogenic Right Ventricular Cardiomyopathy: Most Common Genetic Causes

Gene 1Proportion of ARVC Attributed to Pathogenic Variants in This Gene 2Proportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
DSC21%-2%>90% 6Unknown 7
DSG25%-26%>90% 6Unknown 7
DSP2%-39%>90% 60%-8% 8
JUP0.5%-2%>90% 6Unknown 7
PKP234%-74%>80% 611.7%
TMEM43Rare>90% 6Unknown 7
Unknown 9NA

Pathogenic variants of any one of the genes listed in this table account for ≥1% of ARVC; genes are listed in alphabetic order.

1.
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 pathogenic variants are identified

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Bao et al [2013], Rigato et al [2013], Groeneweg et al [2015], Lazzarini et al [2015]. The proportion of ARVC attributed to specific genes varied by cohort studied, suggesting that the relative contribution of the different genes associated with ARVC may differ based on ethnicity and also on the medical care setting at the time of diagnosis (since the criteria for diagnosis of ARVC and for genetic testing may differ).

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

8.
9.

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: ARVD3 (14q12-q22) [Severini et al 1996], ARVD4 (2q32.1-q32.3) [Rampazzo et al 1997], ARVD6 (10p14-p12) [Li et al 2000, Matolweni et al 2006].

Table 1b.

Molecular Genetics of Arrhythmogenic Right Ventricular Cardiomyopathy: Less Common Genetic Causes

Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of ARVC) and the syndromes associated with these genes may overlap with the broader disorder, arrhythmogenic cardiomyopathy. Genes are listed in alphabetic order.

1.
2.

Click here (pdf) for further information on some of the genes included in the table.

Note:

(1) Molecular genetic testing should be considered in individuals who are suspected of having ARVC based on international task force criteria [Marcus et al 2010], but who do not meet criteria for a definite clinical diagnosis*. For some of these individuals, identification of a pathogenic variant in one of the ARVC-related genes fulfills the remaining criteria (see Suggestive Findings).

*Borderline diagnosis of ARVC:

  • One major AND one minor criterion; OR
  • Three minor criteria from different categories

*Possible diagnosis of ARVC:

  • One major criterion; OR
  • Two minor criteria from different categories

(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 pathogenic variant in an individual who meets diagnostic criteria, the clinical diagnosis of ARVC is unchanged.

Beyond the Diagnostic Criteria: Additional Information

Note: The phenotype of ARVC is widely variable and some affected individuals may not meet the specific criteria [McKenna et al 1994, Marcus et al 2010]; however, such individuals may still be at risk for cardiovascular events including arrhythmias and, therefore, warrant continuing care by a cardiologist.

Additional considerations regarding the noninvasive and invasive tests of cardiac structure and rhythm are outlined here (pdf).

Clinical Characteristics

Clinical Description

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disorder affecting the right ventricle and in some cases also the left ventricle. ARVC is progressive and characterized by fibrofatty replacement of the myocardium, predisposing to ventricular tachycardia and sudden death in young individuals [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 ARVC most frequently arise from the right ventricle and have left bundle branch block morphology.

Pathology in ARVC may also extend to involve the left ventricle [Horimoto et al 2000, Hamid et al 2002]. Cardiac MRI studies have identified regional left ventricular dysfunction in individuals with ARVC [Sen-Chowdhry et al 2006, Jain et al 2010]. Delayed enhancement may also be seen in the left ventricle [Marra et al 2012].

Presentation. The most common presenting symptoms are heart palpitations, syncope, and death. As expected, probands/index cases have a more severe presentation. See Penetrance.

Age at diagnosis and survival. ARVC typically presents in adults, although it may be seen in children during the second decade. Two long-term studies following individuals with ARVC suggest that survival is greater than 72% after six years of follow up. In ARVC overall, cardiac mortality and need for transplant are less than 5% [Bhonsale et al 2015, Groeneweg et al 2015].

Gender differences. Males are more likely to present as probands with ARVC, although females constituted nearly half of a large cohort (45%) [Bhonsale et al 2015]. In a multivariate analysis of indviduals with genetically confirmed ARVC, male sex was more likely to associate with arrhythmia events [Protonotarios et al 2016].

Progression. The four described stages of ARVC [Dalal et al 2006]:

1.

Concealed phase (no clinical manifestations of ARVC, but potential risk of sudden cardiac death)

2.

An overt electrical disorder (characterized by symptomatic arrhythmias)

3.

Right ventricular failure

4.

A biventricular pump failure (resembling dilated cardiomyopathy) [Dalal et al 2006]

Left ventricle involvement can occur at any of the above stages [Sen-Chowdhry et al 2007].

Symptomatic arrhythmia. Symptomatic arrhythmias include palpitations, syncope, and presyncope attributable to ventricular ectopy or sustained or nonsustained ventricular tachycardia.

Arrhythmia and sudden death. 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 ARVC is thought to relate to sudden ventricular arrhythmias.

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

  • Bhonsale et al [2015] evaluated 541 individuals (220 probands and 321 family members); 53% were asymptomatic at the time of first evaluation. Twenty-five percent presented with sustained ventricular tachycardia; this included 54% of probands versus 4% of family members. The median age range at symptom onset was 30 years (range 10-84 years). Of the overall cohort, 30% had spontaneous sustained VT over the follow up of six years.
  • Rigato et al [2013] examined a cohort of 113 individuals of whom 84% had a single desmosomal gene variant and 16% had compound heterozygous or digenic inheritance. Over an observation period that averaged 39 years, 16% had major arrhythmic events. Specific risk factors for having events were male sex and having multiple genetic variants.
  • Groeneweg et al [2015] reviewed the outcomes in a cohort of 439 individuals who met task force criteria and 562 family members. Over a median follow-up interval of seven years, 72% of living probands experienced sustained ventricular arrhythmias. Of family members of probands who carried pathogenic variants, 11% experienced ventricular arrhythmias over the follow-up interval.
  • Protonotarios et al [2016] followed 105 individuals with desmosomal gene variants finding that males were more likely to have an arrhythmic event than females. Furthermore, 41% experienced a primary arrhythmic event by age 29 (range 21-46 years). Of note, definitive diagnosis by task force criteria in the presence of a desmosomal variant showed a 57% positive and 100% negative predictive value for the occurrence of an arrhythmic event.

Cardiomyopathy. The cohort of individuals with ARVC followed by Bhonsale et al [2015] had an overall incidence of left ventricular dysfunction of 14% over the follow-up interval, with 5% experiencing heart failure.

Genotype-Phenotype Correlations

Few genotype-phenotype correlations have emerged correlating specific ARVC genotypes to clinical outcomes. One observation is that DSP variants are more likely to be associated with left ventricular dysfunction [López-Ayala et al 2014, Bhonsale et al 2015]. A second observation is that having more than one variant increases propensity to arrhythmias and progression to cardiomyopathy [Bao et al 2013, Rigato et al 2013, Bhonsale et al 2015, Groeneweg et al 2015]. It has also been suggested that PKP2 pathogenic variants are more likely to be associated with ventricular tachycardia [Bao et al 2013].

Penetrance

Probands are more likely to have ventricular arrhythmias than their family members [Groeneweg et al 2015]. Of family members with a pathogenic variant, 324 of 385 were asymptomatic, and of these 324 asymptomatic subjects, 221 (68%) did not meet task force criteria. Therefore, penetrance for ventricular arrhythmias appears to be relatively low in this disorder.

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 term ARVC is favored.

Prevalence

The prevalence of ARVC is estimated at 1:1000 to 1:1250 in the general population [Peters 2006].

The prevalence of ARVC 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

ARVC and anterior polar cataract (APC). A single family with ARVC and subscapular cataract, a rare hereditary form of lens opacity, has been described [Frances et al 1997]. The proband and his sister both had ARVC and APC. The gene responsible for APC previously was linked to 14q24qter. Parents of the sibs were second cousins (OMIM 115650).

DES. Pathogenic variants in DES have been associated with:

It is unknown at this point whether unique DES variants cause the ARVC phenotype; however, pathogenic variants in the DES regions encoding both the head and tail of desmin have been identified as causative of ARVC in association with desminopathy [van Tintelen et al 2009, Otten et al 2010].

Cardiomyopathy. Many forms of cardiomyopathy may mimic aspects of ARVC. Cardiomyopathies may arise from genetic, toxic, or immunologic insults. Clinical testing may be useful to distinguish cardiomyopathy from ARVC. 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 ARVC.

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 ARVC. Clinical testing may be useful to distinguish these from ARVC.

Right ventricular outflow tract tachycardia (RVOT) is a clinical arrhythmia condition that is not typically associated with structural heart disease as is seen in ARVC. 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 ARVC is rarely seen in Brugada syndrome.

Sarcoidosis. The fibrofatty infiltration of the heart characteristic of ARVC may resemble noncaseating granulomas seen on MRI in cardiac sarcoidosis [Dechering et al 2013].

Intense exercise. ARVC is present in 4%-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 promotes the manifestation of ARVC. 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]. Sequence analysis of five genes that encode desmosomal proteins (DSC2, DSG2, DSP, JUP, and PKP2) revealed lower than expected variant rates, particularly in athletes performing the most exercise. More recently, a study of individuals with ARVC found that a history of intense exercise (e.g., endurance running) resulted in an earlier age of onset of ARVC [James et al 2013].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC), 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
  • Noninvasive monitoring. Cardiac rhythm can be monitored noninvasively through Holter or event monitoring, and this is an effective means of detecting ventricular ectopy including nonsustained ventricular tachycardia. Implantable loop recorders can also be used in individuals with ARVC for whom arrhythmia risks are not clear. Signal-averaged ECGs may also be useful [Philips & Cheng 2016].
  • Electrophysiology study to assess the risk for ventricular arrhythmias and the appropriateness of device insertion (e.g., an implantable cardioverter defibrillator). A cardiac catheter ablation of tissue causing abnormal rhythms can be performed during the electrophysiology study; however, ablation may not be effective long term in individuals with ARVC because of the multiple sites of primary ventricular tachycardias.

Treatment of Manifestations

Affected individuals should be monitored by a cardiologist who is knowledgeable about ARVC. Management of individuals with ARVC is complicated by its variable course and the limited specificity of clinical findings to predict arrhythmia risk. Management should be individualized and based on the specific results of detailed clinical and genetic investigation.

  • Management is focused on prevention of syncope, cardiac arrest, and sudden death (see Prevention of Primary Manifestations).
  • Beta blockers are considered first line therapy. Although their efficacy has not been shown in a randomized, prospective clinical trial, beta blockers are recommended [Yancy et al 2013, Corrado et al 2015].
  • Amiodarone may also be effective [Corrado et al 2015].
  • The mainstay of arrhythmia prevention relies on device insertion and management. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias.

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

Physical exercise ‒ specifically regular, intense exercise ‒ is thought to promote ARVC and its associated arrhythmias. Therefore, those with fully diagnosed ARVC are usually recommended to reduce or eliminate prolonged exercise and participation in competitive sports [James et al 2013]. Supporting this idea that intense exercise hastens the onset of ARVC, Ruwald et al [2015] reported that a history of participation in competitive sports was associated with an earlier age of onset. These findings support the notion that intense exercise can induce ARVC even in the absence of an identifiable genetic predisposition.

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

Prevention of Primary Manifestations

Prospective randomized trials have not been conducted in ARVC for the prevention of arrhythmias. Management relies on personalized recommendations based on clinical assessment.

Implantable cardioverter-defibrillators (ICDs). Observational studies support that ICD placement is effective in reducing the risk for sudden cardiac death in ARVC. ICD placement should be considered in anyone with a clinical diagnosis of ARVC. Corrado et al [2010] reported results of ICD implantation in 106 individuals with ARVC who met task force criteria. Device placement was based on the presence of arrhythmia risk factor defined as syncope, family history of sudden death, nonsustained ventricular tachycardia, and whether ventricular tachycardia or fibrillation was inducible in an electrophysiology done at the time of device implant. Over the follow-up interval of 58 months, 24% of subjects had an appropriate ICD discharge. Syncope was found to predict appropriate ICD discharge. The advisability of placing an ICD for primary prevention remains a question of debate [Zorzi et al 2016].

The ACC/AHA (American College of Cardiology/American Heart Association) and European Society of Cardiology (ESC) guidelines, which are based on experience and previously published reports 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 have a reasonable expectation of survival with 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), family members with sudden death, or undiagnosed syncope when ventricular fibrillation or ventricular tachycardia cannot be excluded as the cause of syncope while the individual was on optimal medical therapy [Tracy et al 2013, Priori et al 2015].

Surveillance

Screening for degree of cardiac involvement in persons diagnosed with ARVC 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, event monitoring, implantable loop recorder
  • Exercise stress testing
  • Cardiac MRI, with frequency depending on symptoms and findings

Agents/Circumstances to Avoid

Individuals with ARVC are discouraged from participating in vigorous athletic activity including competitive athletics because of the strain caused on the right heart [Corrado et al 2015].

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to relatives at risk for ARVC (even those age <18 years) if the pathogenic variant(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: The initial molecular testing in the proband should encompass ARVC-related genes as a gene panel because of the high rate of digenic heterozygosity (a heterozygous pathogenic variant in two different genes) and to increase the yield of genetic testing [Barahona-Dussault et al 2010, Bauce et al 2010, Christensen et al 2010, Xu et al 2010, Nakajima et al 2012]. Once one (or more) family-specific variant(s) have been identified, targeted variant testing is performed in relatives.

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

  • If the family-specific pathogenic variant 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 pathogenic variant 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
  • 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].

Children younger than age ten are not usually screened, as ARVC features are not usually seen in children before this age. See Hamilton & Fidler [2009] for a review of screening for ARVC in the young. A recent MRI study of ARVC in the young suggested that MRI increases sensitivity but that it was still unusual, even with this more sensitive modality, to see ARVC in children before age ten years [Etoom et al 2015].

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

Pregnancy Management

Case reports describe successful outcomes in women with ARVC who are pregnant and give birth [Agir et al 2014, Cozzolino et al 2014]. Specific guidelines for managing ARVC in pregnancy have not been developed, but affected individuals need to be monitored by a multidisciplinary team.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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 cardiomyopathy (ARVC) 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 ARVC, 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 ARVC inherited a pathogenic variant from a heterozygous parent.
    • If a proband has two pathogenic variants in the same ARVC-related gene, both parents may be heterozygous or, less commonly, one parent has two pathogenic variants on the same allele.
    • Both parents should undergo confirmatory genetic testing to allow accurate inheritance and risk counseling. How often this form of inheritance arises from the contribution of only parent or both parents is not well defined.
  • Parents who are heterozygous for an ARVC pathogenic variant may or may not have clinical findings.
  • A proband with autosomal dominant ARVC may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
    Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant (i.e., neither parent is known to be affected) include cardiac MRI or echocardiogram, ECG, and molecular genetic testing if the pathogenic variant(s) have been identified in the proband.
  • The family history of some individuals with ARVC 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 one parent of the proband is affected and/or has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. If both parents have a pathogenic variant, the risk to sibs of inheriting two pathogenic variants is 25%, one variant is 50%, and neither variant 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 one ARVC-related pathogenic variant has a 50% chance of inheriting the pathogenic variant.
  • Each child of an individual with biallelic ARVC-related pathogenic variants will inherit one pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected or has a pathogenic variant, his or her family members are at risk.

Risk to Family Members — Digenic Inheritance

Digenic ARVC results from the presence of two pathogenic variants: one variant in one ARVC-related gene plus another variant in a different ARVC-related gene. Estimates of digenic inheritance vary, ranging from 4% to 47% [Xu et al 2010, Bao et al 2013, Rigato et al 2013, Bhonsale et al 2015, Groeneweg et al 2015].

Parents of a proband

  • Typically, one parent has an ARVC-related pathogenic variant in one gene and the other parent has an ARVC-related pathogenic variant in a different gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent harbors both pathogenic variants.
  • The parents may or may not have clinical findings.

Sibs of a proband. Assuming that each parent has one pathogenic variant, at conception each sib has a 75% chance of inheriting one or two ARVC-related variants (and being at increased risk of developing ARVC) and a 25% chance of not inheriting a pathogenic variant (and being unaffected).

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

Other family members. Each sib of the proband’s parents will have zero, one, or two ARVC-related pathogenic variants 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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ARVC-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ARVC are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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.

  • My46 Trait Profile
  • 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 #202
    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 Cardiomyopathy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Arrhythmogenic Right Ventricular 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 cardiomyopathy (ARVC). This is suggested by pathogenic variants in the subset of ARVC-related genes encoding desmosomal proteins, desmoplakin (DSP), desmocollin 2 (DSC2), desmoglein 2 (DSG2), plakophilin 2 (PKP2), α-catenin (CTNNA3), and plakoglobin (JUP).

Altered calcium homeostasis may provide another pathogenic pathway in ARVC as suggested by pathogenic variants in RYR2. RYR2 has an important role in calcium release from the sarcoplasmic reticulum and the regulation of excitation-contraction coupling. Impaired intracellular calcium content 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 variants in the genes can be found in the Leiden Open Variation Database or the ARVD/C Genetic Variants Database (www.arvcdatabase.info) [van der Zwaag et al 2009, Lazzarini et al 2015]. (Links to this database are found in Table A under LSDB.)

The results of several studies suggest that interpreting sequence variation for ARVC pathogenesis is challenging as some previously designated pathogenic variants are found in the general population [Kapplinger et al 2011, Lahtinen et al 2011, Andreasen et al 2013]. Interpretation of pathogenicity of genetic variants must always be done in the context of careful phenotyping.

DSC2

Gene structure. The transcript variant NM_024422.4 has 16 exons and encodes the longer desmocollin-1 protein isoform DSC2a (NP_077740.1). The transcript variant NM_004949.4 contains an additional exon at the 3’ end resulting in a frameshift and a shorter desmocollin-1 protein isoform, DSCb (NP_004940.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 50 pathogenic variants have been described (see Table A, Locus Specific). In addition, multiple instances of digenic inheritance have been identified with DSC2 variants along with other desmosomal gene mutations [Bhuiyan et al 2009, Groeneweg et al 2015] and compound heterozygosity [Lorenzon et al 2015] and homozygosity [Wong et al 2014].

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, DSC2a and DSC2b, produced by alternate splicing of exon 16; the preproproteins are 901 and 847 amino acids, respectively, and are proteolytically processed to generate the mature protein. 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 pathogenic isoforms that lack the last 37 amino acid residues of the carboxyl-terminal domain of DSC2a are unable to bind plakoglobin. It is unknown how the variants affect desmosome formation, but it is speculated that the result would be impaired desmosome structure or function.

DSG2

Gene structure. The gene comprises 15 exons spanning 48.6 kb; the transcript is NM_001943.4. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. More than 20 benign variants have been reported in DSG2 (www.arvcdatabase.info)

Pathogenic variants. More than 20 pathogenic variants have been described (see Table A, Locus Specific) In addition, multiple instances of digenic inheritance have been identified with other desmosomal gene variants [Rigato et al 2013, Groeneweg et al 2015]. Biallelic inheritance has also been described in ARVC with compound heterozygous variants [Awad et al 2006, Pilichou et al 2006, Bhuiyan et al 2009].

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]. The preproprotein has 1118 amino acids (NP_001934.2) and is proteolytically processed to generate the mature glycoprotein.

Abnormal gene product. Much of the underlying pathogenesis of DSG2 pathogenic variants is still unknown; it is believed that loss of DSG2 compromises cell-to-cell adhesion between cardiomyocytes [Kant et al 2015].

DSP

Gene structure. The longest transcript variant (NM_004415.3) comprises 24 exons and encodes the desmoplakin protein of 2871 amino acids (NP_004406.2). For a detailed summary of gene and protein information, see Table A, Gene.

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

Pathogenic variants. More than 80 pathogenic variants have been described (see Table A, Locus Specific). In addition, multiple instances of digenic inheritance have been identified with other desmosomal gene mutations [Rigato et al 2013, Groeneweg et al 2015].

Normal gene product. Desmoplakin is a component of the desmosome. Desmosomes are major cell-cell junctions, particularly abundant in epidermal cells and in cardiomyocytes [Gallicano et al 1998, Smith & Fuchs 1998]. Desmoplakin, together with plakoglobin, anchors to desmosomal cadherins, forming an ordered array of non-transmembrane proteins, which then bind to keratin-intermediate filaments [Kowalczyk et al 1997, Smith & Fuchs 1998, Leung et al 2002]. Within the desmosome, desmoplakin links the cadherin, plakoglobin, PKP complex to the intermediate filament. The structure of desmoplakin is a large N-terminal domain, a central coiled coil rod that dimerizes the molecule and a C-terminal region that binds to the intermediate filament [Choi & Weis 2016].

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 de-differentiation of myocytes into adipocytes [Garcia-Gras et al 2006]. Conditional deletion of Dsp using the Hcn4-Cre allele, which deleted Dsp in the cardiac conduction system, resulted in sinus node dysfunction, underscoring the importance of desmosomes for cardiac conduction system integrity [Mezzano et al 2016].

JUP

Gene structure. The transcript variant NM_002230.2 comprises 14 exons, the first one being noncoding. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. One benign variant (c.2089A>T) has been identified as cosegregating with a variant in desmoplakin. The frequency of genotypes at position 2089 in the Turkish population is 0.57/0.36/0.07 respectively for genotypes TT/AT/AA [Uzumcu et al 2006]. See ARVD/C Genetic Variants Database for additional allele frequencies and publications. The benign variant c.2089T>A is located at position +4 after the acceptor site in exon 3; 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.

Pathogenic variants. More than 15 pathogenic variants have been described (see Table A, Locus Specific)

Table 3.

Selected JUP Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein 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 (varnomen​.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 transcript NM_002230.2 encodes junction plakoglobin, a cytoplasmic protein also known as gamma catenin, which is found in both submembranous plaques of desmosomes and intermediate junctions. The protein forms distinct complexes with cadherins and desmosomal cadherins. It has 745 amino acids (NP_002221.1) with a distinct repeating amino acid motif called the armadillo repeat. Swope et al [2012] identified a relationship between plakoglobin and β-catenin such that both normal proteins are necessary to a normal functioning gap junction [Swope et al 2012].

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 pathogenic variants in JUP affect 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]. Genetic fate mapping in mice using fluorescent reporters and conditional deletion suggest that the origin of adipogenic cells in ARVC is the second heart field, which are then reprogrammed to an adipogenic fate through suppressed Wnt signaling via nuclear plakoglobin [Lombardi et al 2009].

PKP2

Gene structure. The longer transcript variant NM_004572.3 comprises 14 exons. Note that a processed pseudogene with high similarity to this locus has been mapped to chromosome 12p13. For a detailed summary of gene and protein information, see Table A, Gene.

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

Pathogenic variants. More than 170 pathogenic variants have been described, including gross deletions [Li Mura et al 2013, Roberts et al 2013] (see Table A, Locus Specific). Multiple instances of digenic inheritance have been identified with one pathogenic variant in PKP2 and a second in another desmosomal gene [Cox et al 2011, Bao et al 2013, Bhonsale et al 2015, Groeneweg et al 2015].

Normal gene product. NM_004572.3 encodes plakophilin-2 isoform 2b of 881 amino acids (NP_004563.2). 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.

TMEM43

Gene structure. The TMEM43 transcript variant NM_024334.2 comprises 12 exons that encode a protein of 400 amino acids (NP_077310.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. One putative pathogenic variant, the missense change p.Ser358Leu, was identified in a number of families, the majority of which were of Newfoundland ancestry [Merner et al 2008, Christensen et al 2011, Baskin et al 2013]. This variant may relocate proteins essential for cardiac conduction, thereby altering gap junction function to reduce cardiac conduction velocity [Siragam et al 2014].

Table 4.

Selected Pathogenic TMEM43 Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1073C>Tp.Ser358LeuNM_024334​.2
NP_077310​.1

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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. TMEM43 codes for a novel protein designated as transmembrane protein 43, which localizes to the membrane of the nuclear envelope and the endoplasmic reticulum. TMEM43 interacts with emerin and lamins A and B and may be a binding partner in the LINC complex (linker of the nucleoskeleton and cytoskeleton) [Bengtsson & Otto 2008, Meinke et al 2011].

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

Additional Genetic Causes of ARVC

For further information on genes listed in Table 1b click here (pdf).

References

Published Guidelines/Consensus Statements

  • Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). 2011. [PubMed: 21787999]
  • Corrado, D, Wichter T, Link MS, Hauer RN, Marchlinski FE, Anastasakis A, Bauce B, Basso C, Brunckhorst C, Tsatsopoulou A, Tandri H, Paul M, Schmied C, Pelliccia A, Duru F, Protonotarios N, Estes NM 3rd, McKenna WJ, Thiene G, Marcus FI, Calkins H. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: an international task force consensus statement. Available online. 2015. Accessed 2-28-18.
  • 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. 2010. [PMC free article: PMC2848326] [PubMed: 20172912]
  • Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Available online. 2015. Accessed 2-28-18. [PubMed: 26318695]

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Suggested Reading

  • Haugaa KH, Haland TF, Leren IS, Saberniak J, Edvardsen T. Arrhythmogenic right ventricular cardiomyopathy, clinical manifestations, and diagnosis. Europace. 2016;18:965–72. [PubMed: 26498164]

Chapter Notes

Acknowledgments

This work was supported by the National Institutes of Health.

Revision History

  • 25 May 2017 (ha) Comprehensive update posted live
  • 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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