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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

With genetics implicated in so many of the cardiomyopathies, genetic screening has taken on an increasing role alongside taking a thorough family history.

"The possibility of an inherited cardiomyopathy provides the impetus for cascade screening of undiagnosed family members, thereby potentially avoiding preventable adverse events in affected relatives by implementation of GDMT [guideline-directed medical therapy] and other management that otherwise would not be initiated," according to updated multisociety heart failure guidelines released in conjunction with the American College of Cardiology meeting in April 2022.

Who to Screen

The guidelines gave a class 1 recommendation to genetic screening and counseling for first-degree relatives of "selected" patients with genetic or inherited cardiomyopathies.

Factors the guidelines panel cited as pointing to a possible genetic cause of cardiomyopathy included the following:

• Cardiac morphology with marked left ventricular (LV) hypertrophy, LV noncompaction, or right ventricular thinning or fatty replacement on imaging or biopsy

• 12-lead ECG showing abnormally high or low voltage or conduction, and repolarization, altered right ventricular forces

• Frequent nonsustained ventricular tachycardia or very frequent premature ventricular contractions

• Early onset of conduction disease or atrial fibrillation

• Extra-skeletal features, such as skeletal myopathy, neuropathy, or cutaneous stigmata

"The second element, which cannot be overemphasized, is a comprehensive family history that spans at least three generations," noted a 2020 from the American Heart Association (AHA) on genetic testing for inherited cardiomyopathies.

A family history, the 2022 heart failure guidelines added, should ask specifically about family members with cardiomyopathy, an enlarged or weak heart, recurrent syncope, sudden death, unexplained death from drowning or a single-vehicle crash, a pacemaker or atrial fibrillation on its own before age 65, and any type of skeletal muscle disease, like Duchenne.

A younger age at the onset of those events makes a genetic cause more likely, with the exception of hereditary amyloidosis, for which the cardiac and peripheral manifestations may present in later life, the writers pointed out.

Why to Screen

The guidelines also gave a class 2a recommendation for referral to genetic counseling and testing for select patients with non-ischemic cardiomyopathy as "reasonable" to identify conditions that could guide treatment for those patients and their family members.

However, the patient who presents first in the family isn't always the best one to screen first for genetic causes, the scientific statement noted. "For reasons of practicality, the provider often will need to test the patient presenting to the clinic first, but in principle, the family member with the most definitive and most severe phenotype should be the one initially tested to increase the chances of identifying pathogenic variant(s) useful for familial testing."

The higher class of recommendation for screening patients' parents, siblings, and children was to detect cardiac disease and potentially step in with medications or other interventions to decrease heart failure progression and prevent sudden death.

In a Japanese of 514 patients with dilated cardiomyopathy (DCM), 7.4% had at least one first-degree relative or an aunt, uncle, grandparent, grandchild, niece, nephew, or half-sibling with DCM. Those patients had a 4.48-fold higher risk of sudden cardiac death or heart failure death compared with patients without a relative who had DCM.

In a of 487 DCM patients in Italy and the U.S. (none with arrhythmogenic right ventricular cardiomyopathy), 37% had pathogenic or likely pathogenic variants found with next-generation sequencing. At the time when that study was published in 2019, more than 50 genes were considered to be disease-related, with causative variants identifiable in approximately 20% to 50% of all DCM cases, the researchers noted.

Limitations of Screening

increased the clinical sensitivity several-fold in another study, but increased the number of inconclusive cases even more so.

"The natural temptation might be to test more genes, perhaps all genes, with the thinking that more data are better, especially because next-generation sequencing has made even complete genome sequencing relatively affordable," the AHA scientific statement noted.

However, it added, "panels that include genes with little support for the gene-phenotype association under investigation may not increase the likelihood of clinically actionable results in adult patients. In addition, expanded test panels may increase the number of variants of uncertain significance identified and, for exome or genome sequencing, may increase the chance of picking up secondary or incidental findings that are not relevant to the disease in question. This can lead to confusion and uncertainty."

When variants of uncertain significance (VUS, those with conflicting reports of pathogenicity or that are in uncharacterized parts of the protein) do turn up, a recent suggested holding on to that variant information to reanalyze as the evidence base improves. Some cases might also benefit from whole-genome or whole-exome sequencing.

A negative result, finding only variants that are likely benign, in the person tested might still prompt an offer of clinical surveillance for first-degree relatives and, in certain cases, whole-genome or whole-exome sequencing to try to find the cause of the clinical phenotype.

The likelihood of finding variants that are pathogenic (or likely so) with next-generation sequencing, according to the review, is:

• About 30% in dilated cardiomyopathy

• 50-60% in hypertrophic cardiomyopathy

• About 50% in arrhythmogenic cardiomyopathy

• About 40% in pediatric cardiomyopathy

• Unknown in restrictive cardiomyopathy

When the result is positive, there's a risk of discrimination based on the genetic findings -- a risk that needs to be discussed with patients before testing. The scientific statement noted that U.S. law protects against genetic discrimination in health insurance and employment, "but it does not apply to other types of insurance (e.g., life and disability), nor does it apply to companies with <15 employees."

At the same time, there are potential benefits in terms of actionable findings.

While the heart failure guidelines cautioned that clinical benefits of genetic testing for cardiomyopathy have yet to be shown in controlled studies, the document noted that "genetic testing contributes to risk stratification and has implications for treatment, currently most often for decisions regarding defibrillators for primary prevention of sudden death and regarding exercise limitation for hypertrophic cardiomyopathy and the ," which are implicated in arrhythmogenic cardiomyopathy.

Impact on Clinical Care

In the U.S. and the Italian DCM study, patients with desmosomal and had the greatest risk for sudden cardiac death and life-threatening ventricular arrhythmias, regardless of LV ejection fraction.

The heart failure guidelines suggested that finding sudden death-associated pathogenic variants may prompt consideration of implantable cardioverter-defibrillator (ICD) placement, "even in patients who have LVEF >0.35 or <3 months of guideline-recommended therapies."

Hypertrophic cardiomyopathy (HCM) guidelines, though, caution against clinical use of determining risk of sudden cardiac death based on carrying more than one pathogenic or likely pathogenic variant. "Similarly, a genetic result in isolation does not influence decisions related to implanting an ICD in patients with HCM," the document added, pointing to "considerable heterogeneity within and between families with variants in the same gene that currently limits the application of genetic information for clinical decision-making, including risk stratification for SCD in the proband."

Confirming symptomatic Fabry's cardiomyopathy, implicated in up to 1% of hypertrophic cardiomyopathy cases, with genetic testing can open up treatment options for enzyme replacement therapy with agalsidase beta (Fabrazyme) and enzyme activity booster migalastat (Galafold).

For transthyretin cardiac amyloidosis patients, TTR gene sequencing gained a class 1 recommendation to differentiate hereditary cases from wild-type transthyretin cardiac amyloidosis. Finding TTR variants should trigger genetic counseling and potential screening of family members and also puts patients in line for treatment with inotersen (Tegsedi) and patisiran (Onpattro), which are approved only for polyneuropathy of hereditary ATTR amyloidosis.

Clinical genetics "is in rapid flux," the scientific statement noted. "Reliable classification of variants identified in genetic testing will remain a preeminent challenge for the practice of clinical genetics," but refinement of classification criteria is underway.

Read previous installments in this series:

Part 1: Cardiomyopathy: What are the Signs, What are the Symptoms?

Part 2: Diagnosing Cardiomyopathy: History, Examination, and Testing

Part 3: Cardiomyopathy: Epidemiology, Etiology, and Pathophysiology

Part 4: Case Study: Cardiomyopathy From Epinephrine in Anesthesia

Up next: Cardiomyopathy Outside the Office