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...

Background-Muscle LIM protein (MLP) is an essential nuclear regulator of myogenic differentiation. Additionally, it may act as an integrator of protein assembly of the actin-based cytoskeleton. MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM). MLP is therefore a candidate gene for heritable forms of hypertrophic cardiomyopathy (HCM) and DCM in humans. Methods and Results-We analyzed 1100 unrelated individuals (400 patients with DCM, 200 patients with HCM, and 500 controls) for mutations in the human CRP3 gene that encodes MLP. We found 3 different missense mutations in 3 unrelated patients with familial HCM but detected no mutation in the DCM group or the controls. All mutations predicted an amino acid exchange at highly conserved residues in the functionally important LIM1 domain, which is responsible for interaction with ␣-actinin and with certain muscle-specific transcription factors. Protein-binding studies indicate that mutations in the CRP3 gene lead to a decreased binding activity of MLP to ␣-actinin.