Overview

Substantial progress has been made recently in understanding the genetic basis of cardiomyopathy. Cardiomyopathies with known genetic cause include hypertrophic (HCM), dilated (DCM), restrictive (RCM), arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and left ventricular noncompaction (LVNC). HCM, DCM, and RCM have been recognized as distinct clinical entities for decades, while ARVD/C and LVNC are relative newcomers to the field. Hence the clinical and genetic knowledge for each cardiomyopathy varies, as do the recommendations and strength of evidence.

The evidence indicating that HCM has a genetic basis is extensive: HCM is now understood largely to be a genetic disease of contractile proteins, although less commonly, infiltrative etiologies may also be causative (Table 17.1). The evidence supporting a genetic basis for DCM, after other more common causes have been excluded (e.g., ischemic disease, hypothyroidism, cardiotoxic agents such as doxorubicin), is now substantial for familial dilated cardiomyopathy (FDC), where FDC is defined as DCM of unknown cause in two or more closely related family members (Table 17.2). However, whether sporadic DCM has a genetic basis remains an open question, especially when detectable familial disease has been clinically excluded by testing closely related family members. Thus, while some recommendations formulated for the genetic evaluation of cardiomyopathy, such as the need for family history, apply to all entities, other recommendations must be tailored to account for these differences. This is particularly relevant as these guidelines use the generic term 'cardiomyopathy' to imply possible familial or genetic cause, assuming that all other detectable causes of cardiomyopathy have been ruled out. As noted above, multiple non-genetic causes are possible for DCM.

Recent discoveries indicate that ARVD/C is largely caused by mutations in genes encoding proteins of the desmosome (Table 17.3). Although initially recognized predominantly in the right ventricle, left ventricular involvement in 20-40% of patients has prompted the change in nomenclature from ARVD to ARVD/C.1

Discovering the genetic basis of restrictive cardiomyopathy (RCM) has been more challenging, as RCM is much less common than DCM or HCM, and less commonly presents with familial disease (Table 17.3).

LVNC is an anatomic abnormality of left ventricular myocardial development: left ventricular compaction is incomplete, leaving deep trabeculations in the LV myocardium. LVNC was categorized as a specific type of cardiomyopathy by an expert panel in 20062, and some genetic association has been observed (Table 17.3). Although initially reported to be a rare condition associated with adverse outcome3, more recent reports 4-6 have called into question those preliminary conclusions.7 Three different echocardiographic criteria have been utilized for diagnosis.6 These authors suggested that the diagnostic criteria for LVNC might be too sensitive. Because of the uncertainty of diagnostic standards leading to difficulty clarifying its phenotype, we suggest that the LVNC recommendations be limited to those individuals with only the most prominent disease.

This section organizes recommendations by cardiac phenotype, recognizing that there is substantial overlap among phenotypes and some mutations are associated with more than one phenotype. Because therapeutic decision-making is generally dictated by phenotype, this approach was considered most helpful for the clinician.

The available clinical genetics data for each of the cardiomyopathies varies greatly in content and quality, and thus the quality and certainty of genetic counseling information is also variable. The evidence that supports clinical genetic testing varies greatly. While analytic validity (the ability of the test to detect a mutation) is attainable with current methods, evidence to support clinical validity (the ability of the test to detect the condition) remains quite limited for most cardiomyopathies, the exception being HCM. A separate measurement, clinical utility, defines the global risks and benefits of any test, asking the all-important question: how will the genetic information, whether positive or negative, affect clinical decision-making for the patient or the patient's family? Clinical utility remains to be defined for all genetic testing of cardiomyopathies.

While each recommendation has been designed for adult and pediatric patients, many of the references used to formulate these recommendations have focused primarily on adults. A section devoted to pediatric genetic cardiomyopathies provides additional specific information.

Despite these limitations, recent progress makes it possible to propose recommendations for the genetic evaluation of cardiomyopathy. These recommendations will evolve and mature as more robust clinical genetics knowledge becomes available.