Manifest Disease, Risk Factors for Sudden Cardiac Death, and Cardiac Events in a Large Nationwide Cohort of Predictively Tested Hypertrophic Cardiomyopathy Mutation Carriers: Determining the Best Cardiological Screening Strategy

Study Questions:

What is the best way to screen relatives of patients with hypertrophic cardiomyopathy (HCM) who carry the putative mutation?


A total of 446 mutation-carrying relatives were identified from 166 families with putative pathogenic mutations. These mutation carriers were not known to have a clinical diagnosis of HCM at the time of genetic testing.


Out of 446 mutation carriers, 136 (30%) were diagnosed with HCM at one or more cardiological evaluation(s). Male gender and higher age were associated with manifest disease. Incidence of newly diagnosed manifest HCM was <10% per person-year under the age of 40 years and >10% in older carriers, although numbers were small in carriers <15 years of age. About 23% of carriers, with and without manifest disease, had established risk factor(s) for sudden cardiac death (SCD) (no significant difference). During an average follow-up of 3.5 ± 1.7 years, two carriers, both with manifest disease, died suddenly (0.13% per person-year). A high-risk status for SCD (≥2 risk factors and manifest HCM) was present in 17 carriers during follow-up (2.4% per person-year). Age but not gender was associated with a high-risk status for SCD.


The authors concluded that 30% of carriers had or developed manifest HCM after predictive DNA testing, and risk factors for SCD were frequently present. These data suggest that the SCD risk is low and risk stratification for SCD can be omitted in carriers without manifest disease, and that frequency of cardiological evaluations can possibly be decreased in carriers between 15 and 40 years old, as long as hypertrophy is absent.


HCM is a relatively common disease typically inherited as an autosomal dominant trait. The disease can be caused by mutations in several different genes and the penetrance is highly variable. Thus, optimal screening strategies for relatives of HCM patients remain to be well defined. Although there are currently no therapies proven to affect progression of this disease, implantable cardioverter-defibrillators are effective in preventing SCD in patients deemed to be at high risk. The presence of manifest disease for predicting risk is critical, and supports the primary role of clinical screening for this disease. The optimal frequency of this clinical screening remains to be determined, and may be less than current guidelines recommend. Although not addressed in this study, these findings also raise issues regarding the added clinical utility of genetic testing in general practice when the causative mutation is unknown, especially if there is no family history of sudden death.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, SCD/Ventricular Arrhythmias, Acute Heart Failure

Keywords: Mutation, Follow-Up Studies, Phenotype, Cardiomyopathy, Hypertrophic, Heart Failure, Risk Factors, Genetic Testing, Death, Sudden, Cardiac

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