Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract

Background-With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. Methods and Results-The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (Pϭ0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; Pϭ0.04). 3 Estimates of penetrance have been confined to single-gene studies. With the identification of disease-causing genes, the familial basis of ARVC is increasingly recognized, and the clinical identification of the relatives at risk has become central to management. This study evaluated a large cohort of families with ARVC to investigate the prevalence of mutations in known causal genes, the penetrance and disease expression in both probands and relatives, and the utility of 2010 diagnostic criteria in familial diagnosis. Conclusions-Arrhythmogenic Editorial see p 2661 Clinical Perspective on p 2709 Methods Study SampleThe Heart Hospital, University College London Hospitals (London, UK) is a national referral center for the diagnosis and management of inherited cardiac diseases. Specialist weekly clinics operate for each of inherited cardiomyopathies (hypertrophic, dilated, arrhythmogenic right ventricular). The families were drawn from referrals to the ARVC, inherited arrhythmia, and victims of sudden death clinics. Diagnosis was considered definite when 2 major, or 1 major and 2 minor criteria, or 4 minor criteria from different categories, were fulfilled. Diagnosis was considered borderline when 1 major and 1 minor or 3 minor criteria from different categories were fulfilled. 5 Evidence of disease expression in relatives was defined by the presence of a borderline (incomplete disease expression) or definite diagnosis. All first-degree relatives and second-degree relatives from families in whom a disease-causing mutation was found were invited for prospective evaluation. Clinical EvaluationClinical evaluation included 12-lead ECG, signal-averaged ECG, transthoracic echocardiography, symptom-limited exercise test, and 24-hour ambulatory ECG...

Recent Developments in the Genetics of Cardiomyopathies

“…Quarta et al found that relatives harbouring more than one genetic variant had a significantly increased risk of developing ARVC, an important factor when interpreting the variable expression of disease within families. This study also highlighted that penetrance may be definition-dependent, being greater with the 2010 task force criteria compared to the 1994 criteria in the case of ARVC [44].…”

Arrhytmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C) and Heart Transplantation: Case Series

“…[6][7][8][9][10][11] Our first patient had his genetic screening for mutations of desmosomal proteins, also his father had the same diagnosis, and the third patient had a family history of ARVD/C, and his elder brother managed by medical therapy.…”

“…The second phase symptomatic arrhythmias of RV origin are common and more prominent; the third phase the isolated RV failure and concomitant dysplastic process becomes diffuse with greater dilatation and dysfunction of RV and finally the fourth phase is left ventricular involvement and biventricular failure. [7][8][9][10][11] All three patients had admitted our hospital with either third phase and fourth phase. The presence of biventricular heart failure and intracardiac thrombus formation were identified as high risk group for our patients.…”

Identification of a PKP2 gene deletion in a family with arrhythmogenic right ventricular cardiomyopathy

“…3,7,[16][17][18][19] Frameshift and nonsense mutations account for 35% (79 out of 224) of PKP2 genetic alterations identified in ARVC patients (ARVD/ C Genetic Variants database; http://www.arvcdatabase.info/).…”

“…[16][17][18][19] In a unique systematic study, applying Multiplex Ligationdependent Probe Amplification (MLPA) on 169 Dutch ARVC patients, large copy number variants involving PKP2 gene were detected in three (1,8%) cases. 19 Very recently, a deletion of the entire coding region of PKP2 gene (excluding exon 1) and a 7.9 Mb deletion of chromosome 12p12.1-p11.1 encompassing PKP2 exons 1-14 were identified in two ARVC cases, by chromosomal oligo-array analysis and/or MLPA.…”