Genetic Evaluation of Cardiomyopathy—A Heart Failure Society of America Practice Guideline

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Abstract

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), the guideline has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, because high-throughput sequencing is now feasible for clinical testing and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to managing secondary and incidental sequence findings as recommended by the ACMG is provided.

Section snippets

The Family as the Unit of Care

A critical transition for cardiovascular practitioners who wish to more fully actualize cardiovascular genetic medicine is to adopt the family as the unit of care, a concept inherently understood by genetics professionals. For cardiovascular providers, moving the care paradigm beyond the patient (proband), who often presents with a fully developed phenotype and at times with advanced life-threatening disease, to at-risk relatives is mandatory to fulfill the promises of precision medicine.

Types of Cardiomyopathy

The genetic basis of hypertrophic cardiomyopathy (HCM) is well established as largely a disease caused by mutations in genes encoding sarcomeric proteins. That familial dilated cardiomyopathy (DCM) has a genetic basis is also well accepted. (The term DCM is used herein instead of the more technical attribution “idiopathic dilated cardiomyopathy,” where the other common and easily clinically detected causes of systolic dysfunction such as coronary artery disease, primary valvular or congenital

Approaches to Review and Publication by the ACMG and HFSA

The writing group was established conjointly with the ACMG and HFSA from 2013 to 2015. The approaches to creating, curating, and approving practice guidelines or practice resources for the HFSA and ACMG, respectively, have been outlined in each group's publication. The material covered in this and the companion document24 are congruent with one another. Differences in scope, including supplemental materials, are denoted and cross-referenced.

The writing group was composed of a panel of

Use of Medical Evidence in This Guideline

We address 2 questions here. The 1st question is that of clinical validity: “Does the evaluation or test correlate with the outcome of interest?”25 Because randomized clinical trials evaluating the clinical accuracy of diagnosis with or without a genetic evaluation or genetic testing are not generally feasible, as in the previous guideline1 we have used a different format for level of evidence. By genetic evaluation we mean a systematic approach that includes a comprehensive family history,

Guideline 1

Obtaining a family history of at least 3 generations, including the creation of a pedigree, is recommended for all patients with a primary cardiomyopathy.

Cardiomyopathy PhenotypeLevel of Evidence
Hypertrophic cardiomyopathy (HCM)A
Dilated cardiomyopathy (DCM)A
Arrhythmogenic right ventricular cardiomyopathy (ARVC)A
Restrictive cardiomyopathy (RCM)A
Cardiomyopathies with extracardiac manifestationsA
Left ventricular noncompaction (LVNC)See Background

Guideline 2

Clinical (phenotypic) screening for cardiomyopathy in at-risk 1st-degree relatives is recommended.

Cardiomyopathy PhenotypeLevel of Evidence
Hypertrophic cardiomyopathy (HCM)A
Dilated cardiomyopathy (DCM)A
Arrhythmogenic right ventricular cardiomyopathy (ARVC)A
Restrictive cardiomyopathy (RCM)A
Cardiomyopathies, overlapping, or extracardiacA
Left ventricular noncompaction (LVNC)See Background

Guideline 3

Referral of patients with genetic, familial, or other unexplained forms of cardiomyopathy to expert centers is recommended.

  • 3a.

    Infants and children with cardiomyopathy should be evaluated by clinicians with specific expertise in the recognition and testing of syndromic and nonsyndromic presentations of cardiomyopathy in this age group.

Guideline 4

Genetic testing is recommended for patients with cardiomyopathy.

  • 4a.

    Genetic testing is recommended for the most clearly affected family member.

  • 4b.

    Cascade genetic testing of at-risk family members is recommended for pathogenic and likely pathogenic variants.

  • 4c.

    In addition to routine newborn screening tests, specialized evaluation of infants with cardiomyopathy is recommended, and genetic testing should be considered.

Cardiomyopathy PhenotypeLevel of Evidence
Hypertrophic cardiomyopathy (HCM)A

Guideline 5

Genetic counseling is recommended for all patients with cardiomyopathy and their family members. (Level of Evidence = A)

Guideline 6

Focused cardiovascular phenotyping is recommended when pathogenic or likely pathogenic variants in cardiomyopathy genes, designated for reporting of secondary findings by the ACMG, are identified in an individual.

  • 6a.

    If a cardiovascular phenotype is identified as would be predicted by currently available knowledge of the gene/variant pair, all usual approaches described in this document for a genetic evaluation, including family-based approaches, are recommended.

  • 6b.

    If no cardiovascular disease

Therapy Based on Genetic Evaluation and Cardiac Phenotype

The clinical characteristics associated with variants in some disease genes, when integrated with pedigree data, may directly influence the overall assessment and clinical recommendations for a patient or family.

One gene with substantial evidence fitting this situation is LMNA, which commonly presents with nonsyndromic cardiomyopathy in adult cardiology practice and is well known for progressive conduction system disease (1st-, 2nd-, or 3rd-degree heart block), usually with supraventricular

Guideline 7

Medical therapy based on cardiac phenotype is recommended, as outlined in consensus guidelines. (Level of Evidence = A)

Guidelines for the evaluation and management of patients with cardiomyopathy have been published for HCM,137, 138 DCM,6, 139, 140, 141 and ARVC.142 These guidelines provide comprehensive guidance for care of those who are presymptomatic (stage B heart failure) or have had the onset of symptoms (stage C or D heart failure). Guidelines for the clinical care of patients with RCM

Guideline 8

Device therapies for arrhythmia and conduction-system disease based on cardiac phenotype are recommended, as outlined in consensus guidelines. (Level of Evidence = B)

In brief, ICDs are indicated for secondary prevention of ventricular tachycardia or ventricular fibrillation regardless of the type of cardiomyopathy or degree of ventricular dysfunction. The indications for ICDs for primary prevention of sudden cardiac death in patients with nonischemic cardiomyopathy with reduced LVEF of any

Guideline 9

In patients with cardiomyopathy and significant arrhythmia or known risk of arrhythmia, an ICD may be considered before the LVEF falls below 35%. (Level of Evidence = C)

Electrophysiologic disease can be considered broadly as conduction system disease and arrhythmia (see the discussion above regarding LMNA cardiomyopathy), but this guideline applies to any genetic cardiomyopathy that presents or progresses to lethal arrhythmia or heart block before advanced LV dysfunction. Examples of other

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