1. NGS panel - Genetic testing for Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy

April 11, 2017

Clinical features

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) is a heritable heart-muscle disorder which causes progressive replacement of right ventricular myocardium by fibrofatty tissue. ARVD is an important cause of sudden cardiac death (SCD) in young adults, accounting for 22% of cases among athletes 2 and 11% of all cases 1.

Patients typically present in their second to fifth decade with symptoms associated with ventricular arrhythmias and go on to have an arrhythmic disease course. Sudden cardiac death may be the first manifestation in up to 50 % of index cases 3. ARVD/ARVC is estimated to affect 1:1000 - 1:5000 individuals in the general population 4. It is among the most common causes of sudden cardiac death in people ≤35 years of age 3.

Progressive degeneration of cardiac myocytes with replacement by fat and fibrous tissue is highly characteristic and different than those seen in other cardiomyopathies 5. Structural abnormalities are result of fat infiltration and fibrosis within the right ventricular myocardium and subsequent myocardial loss.

Major clinical features and signs identified in ARVD/ARVC affected patients include right ventricular akinesia, dyskinesia or aneurism accompanied with abnormal sizes of parasternal long and short axes and changes in end-systolic volume and right ventricular ejection fractions (>40%) 6.

Common symptoms experienced by affected patients include the following 7, 8:

  • Palpitation (in 27-67% affected patients)
  • Atypical chest pain (27%)
  • Syncope (26-32%)
  • Dyspnea (11%)
  • Sudden cardiac death (up to 22% in athletes 2, 7, 8)

In many cases ARVD/ARVC is a genetic disorder, with an autosomal dominant pattern of inheritance. Interestingly, on the Greek island Naxos there are numerous familial cases of autosomal recessive ARVD/ARVC, which was appropriately named “Naxos disease”9. In addition to cardiac symptoms, Naxos disease also has features of palmoplantar keratoderma and other ectodermal features, and it was recently associated with mutations in gene encoding plakoglobin (JUP) 9.

In the majority of ARVD/ARVC cases, mutations in genes encoding desmosomal proteins play a key role in the pathogenesis of the disease, including the following: plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2 (DSC2). Additional genes include TGFB3, TMEM43 and RYR2 (see Table 1).

Table 1. Overview of the genes in CENTOGENE´s Arrhythmogenic right ventricular cardiomyopathy

chr. Locus
Protein % of mutations Allelic disorders
DSP 125647
Desmoplakin 1%-16% for ARVD 6 ARVD8, DCWHK, EBLA, PPKS2, SFWHS
DSG2 125671
Desmoglein 2 3%-19% for ARVD 6 ARVD10, CMD1BB
DSC2 125645
Desmocollin 2 1%-13% of all ARVD 6 ARVD11, CMD, ARVC
JUP 173325
Plakoglobin Rare ARVD12, Naxos disease, CMD, EBLA
PKP2 602861
Plakophilin 2 10%-52% for ARVD 6, 9 ARVD9, CMD, CMH, SCFI, BRGDA
RYR2 180902
Ryanodine receptor 2 50%-55% of all CPVT 10 ARVD2, CPVT1, LQTS, BRGDA, SCFI
TGFB3 190230
Transforming growth factor beta-3 Rare ARVD1, LDS5, SCFI, Aortic aneurism
TMEM43 612048
Transmembrane protein 43 Rare ARVD5, EDMD7, SCFI

Abbreviations: LQT: Long QT syndrome; CPVT: catecholaminergic polymorphic ventricular tachycardia; CMH: hypertrophic cardiomyopathy; LGMD: limb-girdle muscular dystrophy; MPDT: Tateyama type of distal myopathy; RMD: Rippling muscle disease; JLNS: Jervell and Lange-Nielsen syndrome; ATFB: familial atrial fibrillation; HALD: familial hyperaldosteronism; CMD: cardiomyopathy dilated; PFHB: progressive familial heart block; SSS: sick sinus syndrome; VF: paroxysmal familial ventricular fibrillation; SIDS: sudden infant death syndrome; ARVD: arrhythmogenic right ventricular dysplasia.; DCWHK: cardiomyopathy dilated with woolly hair and keratoderma; EBLA: lethal acantholytic epidermolysis bullosa; PPKS2: keratosis palmoplantaris striata II; SFWHS: skin fragility-woolly hair syndrome; ATRST: atrial standstill; SCFI: sudden cardiac failure, infantile; GEFSP: generalized epilepsy with febrile seizures plus; EIEE: epileptic encephalopathy, early infantile; LDS: Loeys-Dietz syndrome; EDMD: Emery-Dreifuss muscular dystrophy.

The main goal of treatment of arrhythmogenic right ventricular dysplasia/cardiomyopathy is the prevention of sudden cardiac death. Implantable cardioverter defibrillator (ICD) is the only proven "lifesaving" therapy. Other treatment options, such as life style changes, antiarrhythmic drugs, beta-blockers and catheter ablation, may reduce the arrhythmic burden and alleviate symptoms.

CENTOGENE experts have designed an arrhythmogenic right ventricular cardiomyopathy panel which includes the genes: DSP, DSG2, DSC2, JUP, PKP2, RYR2, TGFB3, TMEM43 (see Table 1). CENTOGENE offers arrhythmogenic right ventricular cardiomyopathy panel, including sequencing and deletion/duplication analysis of selected genes (DSG2, TGFB3, JUP, RYR2, PKP2, DSC2, DSP). In addition, any of the genes in the arrhythmogenic right ventricular cardiomyopathy panel can also be ordered individually, for sequencing and deletion/duplication analysis.

Differential diagnosis

The differential diagnosis of arrhythmogenic right ventricular cardiomyopathy panel-related disorders – depending on the major symptoms in the initial case – includes the following diseases 1, 3:

  • ARVD/C and anterior polar cataract (APC)
  • Myofibrillar myopathy caused by mutations in DES
  • Dilated or hypetrophic cardiomyopathy
  • Acute myocarditis
  • Coronary artery disease and myocardial infarction
  • Brugada syndrome

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Arrhythmogenic right ventricular cardiomyopathy using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Arrhythmogenic right ventricular cardiomyopathy panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Arrhythmogenic right ventricular cardiomyopathy panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for this particular gene testing

  • Individuals with a family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s arrhythmogenic right ventricular cardiomyopathy panel can be found in our genetic test catalogue.