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Objective: A predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this study were to examine the phenotypes associated with sarcomere protein (SP) gene mutations and test the hypothesis that variation in non-sarcomere genes modifies the phenotype., Methods: Unrelated and consecutive patients were clinically evaluated and prospectively followed in a specialist clinic. High-throughput sequencing was used to analyse 41 genes implicated in inherited cardiac conditions. Variants in SP and non-SP genes were tested for associations with phenotype and survival., Results: 874 patients (49.6±15.4 years, 67.8% men) were studied; likely disease-causing SP gene variants were detected in 383 (43.8%). Patients with SP variants were characterised by younger age and higher prevalence of family history of HCM, family history of sudden cardiac death, asymmetric septal hypertrophy, greater maximum LV wall thickness (all p values<0.0005) and an increased incidence of cardiovascular death (p=0.012). Similar associations were observed for individual SP genes. Patients with ANK2 variants had greater maximum wall thickness (p=0.0005). Associations at a lower level of significance were demonstrated with variation in other non-SP genes., Conclusions: Patients with HCM caused by rare SP variants differ with respect to age at presentation, family history of the disease, morphology and survival from patients without SP variants. Novel associations for SP genes are reported and, for the first time, we demonstrate possible influence of variation in non-SP genes associated with other forms of cardiomyopathy and arrhythmia syndromes on the clinical phenotype of HCM., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: The aim of this study was to examine the characteristics of non-sustained ventricular tachycardia (NSVT) episodes during Holter monitoring and to determine their relationship to age and prognosis., Background: It has been suggested that NSVT is only of prognostic importance in patients with hypertrophic cardiomyopathy (HCM) when repetitive, prolonged, or associated with symptoms., Methods: We studied 531 patients with HCM (323 male, 39 +/- 15 years). All underwent ambulatory electrocardiogram monitoring (41 +/- 11 h)., Results: A total of 104 patients (19.6%) had NSVT. The proportion of patients with NSVT increased with age (p = 0.008). Maximum left ventricular wall thickness and left atrial size were greater in patients with NSVT. Mean follow-up was 70 +/- 40 months. Sixty-eight patients died, 32 from sudden cardiac death (SCD). Twenty-one patients received an implantable cardioverter defibrillator (ICD). There were four appropriate ICD discharges. In patients < or =30 years (but not >30), five-year freedom from sudden death was lower in those with NSVT (77.6% [95% confidence interval (CI): 59.8 to 95.4] vs. 94.1% [95% CI: 90.2 to 98.0]; p = 0.003). There was no relation between the duration, frequency, or rate of NSVT runs and prognosis at any age. The odds ratio of sudden death in patients < or =30 years of age with NSVT was 4.35 (95% CI: 1.54 to 12.28; p = 0.006) compared with 2.16 (95% CI: 0.82 to 5.69; p = 0.1) in patients >30 years of age., Conclusions: Non-sustained ventricular tachycardia is associated with a substantial increase in sudden death risk in young patients with HCM. A relation between the frequency, duration, and rate of NSVT episodes could not be demonstrated.