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Hypertrophic Cardiomyopathy: Screening of Relatives
Acknowledgment
The authors would acknowledge Dr. Maithri Siriwardena, who was a coauthor of this chapter in the second edition of the textbook.
Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder. The prevalence of overt HCM (using the threshold of a wall thickness of at least 15 mm) is 1 in 500 (0.2%) in the general adult population. Because HCM has an autosomal dominant pattern of inheritance, the offspring of patients with definite HCM have a 50% chance of inheriting a mutation and developing this condition. The screening of first-degree relatives (i.e., children, siblings, parents) of patients with HCM is recommended, and it is a very important aspect of the overall management of patients. The recognition of HCM in family members is particularly imperative because HCM is associated with a risk of sudden cardiac death (SCD). This devastating event occurs at a rate of approximately 1% per year in patients with HCM and is more likely to affect young individuals.
Epidemiology of Hypertrophic Cardiomyopathy
The prevalence of overt HCM of 0.2% in the adult general population is based on echocardiographic and epidemiologic studies published in the 1990s and 2000s and does not include consideration of the prevalence of HCM gene carriers. The phenotypic expression of HCM is not common in children. In terms of the incidence of HCM in children, one study from Australia has reported an annual incidence of HCM of 0.32 per 100,000 in young children (younger than the 10 years of age). Data from the prospective cohort of the North American Pediatric Cardiomyopathy Registry have shown an incidence of 4.7 per 1,000,000 children and adolescents (younger than 18 years of age). However, the cases of HCM in both these studies also included children with malformation syndromes, neuromuscular disorders, or inborn errors of metabolism, conditions that are generally excluded from the definition of familial HCM in adult patients. , ,
Genetics of Hypertrophic Cardiomyopathy
HCM is caused by a mutation in at least one of the genes that encode cardiac sarcomeric proteins or sarcomere-associated proteins. There are at least 11 causative genes associated with HCM: β-myosin heavy chain (MYH7), myosin binding protein C (MYBPC3), troponin T (TNNT2), troponin I (TNNI3), troponin C (TNNC1), α-tropomyosin (TPM1), α-actin (ACTC1), regulatory myosin light chain (MYL2), essential myosin light chain (MYL3), and Z-disc genes. Over the past three decades, more than 1400 mutations (mainly missense mutations) have been detected in patients with HCM. Importantly, HCM caused by a mutation of the sarcomeric proteins is distinct from other inherited causes of left ventricular hypertrophy (LVH) that are related to storage diseases (e.g., Fabry’s disease) or malformation syndromes or multisystem disorders (e.g., Noonan’s syndrome).
Genetic Testing In Hypertrophic Cardiomyopathy
Genetic testing by automated DNA sequencing has extended beyond research settings and is now offered by commercial genetic testing services. The yield of a positive genetic result in a proband (i.e., index patient with HCM) is about 50% because all genes causing HCM have not yet been identified and are absent from testing panels. The type of septal morphology on echocardiography is associated with the likelihood of detecting a genetic defect: one study showed that the yield of genetic testing was 79% in patients with a reverse septal curvature morphology (i.e., predominant midseptal convexity toward the left ventricular [LV] cavity) versus 8% in patients with a sigmoid septal morphology. A larger subsequent study incorporated six clinical and echocardiographic variables, determined from univariate and multivariate analyses, into a genotype predictor score. The four clinical markers in the genotype predictor score are the following: (1) age at diagnosis younger than 45 years, (2) family history of HCM, (3) family history of SCD, and (4) history of hypertension (the latter is a negative predictor of a positive genetic test result). The two echocardiographic markers in the genotype predictor score are (1) the presence of reverse-curve HCM and (2) a maximal LV wall thickness of 20 mm or greater. The yield of a positive genetic test result ranged from 6% to 80%, depending on the number of positive clinical and echocardiographic markers.
Genetic testing is indicated in patients with an atypical presentation of HCM or when another genetic condition (i.e., phenocopy or mimicker of HCM) is suspected. In addition, it is reasonable to perform genetic testing for HCM in the index patient (proband) to facilitate the diagnosis of affected first-degree family members (i.e., cascade [generational] testing or predictive testing), particularly if relatives have negative or indeterminate results from clinical testing. , If a pathogenic mutation is documented in the proband, then first-degree relatives can be offered genetic testing. If no disease-causing mutation is found or if a sequence variant of uncertain significance is reported, then ongoing genetic screening of family members usually cannot proceed. Patients who undergo genetic testing also benefit from genetic counseling. , Because of the limitations of genetic testing, the preferred initial approach to screening family members remains clinical testing with clinical assessment (history and physical examination), 12-lead electrocardiogram (ECG), and two-dimensional echocardiography.
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