Approaches to Genetic Screening in Cardiomyopathies: Key Points

Kontorovich AR.
Approaches to Genetic Screening in Cardiomyopathies: Practical Guidance for Clinicians. JACC Heart Fail 2023;11:133-142.

The following are key points to remember from this review on approaches to genetic screening in cardiomyopathies: practical guidance for clinicians:

  1. Genetic evaluation for cardiomyopathy involves taking a detailed family history, patient counseling on genetic testing, and genetic testing when appropriate.
  2. For cardiomyopathies, large multigene panels are used and collected samples include blood, saliva, or buccal swab. Test results are compared to reference human genome sequencing and variants are classified based on the American College of Medical Genetics and Genomics guidelines into pathogenic, variant of uncertain significance (VUS), or benign.
  3. VUS are typically not useful for cascade testing in relatives due to their uncertainty. However, they may be reclassified over time with the vast majority being classified as benign.
  4. Genetic counselors are specially trained and can assist patients and their families in understanding risks and benefits of genetic testing, collecting detailed family history, and communicating results to patients and families. Bypassing genetic counselors can jeopardize patients’ understanding of testing and decision making.
  5. Genetic cardiomyopathies are associated with variable penetrance (i.e., genotype positive does not imply disease phenotype) and variable expression (i.e., different severity in relatives at different ages despite same genotype). Therefore, relatives with a pathogenic variant need clinical surveillance to allow early treatment once the disease is manifested.
  6. If clinical screening detects early systolic dysfunction, neurohormonal blockade should be initiated. In hypertrophic cardiomyopathy (HCM), mild hypertrophy should warrant consideration of angiotensin receptor blockers that inhibit transforming growth factor-β and delay progression of hypertrophy. An early trial suggested diltiazem use in phenotype-negative genotype-positive carriers for HCM, stabilized wall thickness.
  7. Since not all cardiomyopathies follow Mendelian genetics, some experts suggest relatives testing negative for a single familial pathogenic variant should continue intermittent surveillance, as other undetected variants may pose a risk.
  8. Truncating variants in the titin (TTN) gene are the most common cause for dilated cardiomyopathy (DCM). TTN DCM is associated with a more malignant clinical course than non-TTN DCM.
  9. Lamin A (LMNA) mutation is associated with 100% penetrance. It presents as malignant tachy- or bradyarrhythmia with heart failure. Therefore, a primary prevention implantable cardioverter-defibrillator (ICD) should be considered in LMNA carriers. Some LMNA mutations are associated with muscular dystrophies: specifically limb-girdle/Emery Dreifuss. Competitive exercise has been associated with worse outcomes in LMNA carriers and exercise modification should be recommended.
  10. A specific type of cardiomyopathy associated with SCN5A mutations include frequent multifocal premature ventricular contractions when certain amino acid substitutions result in a new gating pore. Treatment with sodium channel blockers can resolve this.
  11. Desmosomal genes can cause arrhythmogenic right ventricular, left ventricular, or biventricular cardiomyopathy. Truncating mutations in filamin-C (FLNC) share are also associated with high rates of ventricular arrhythmias and an ICD should be considered with moderate systolic dysfunction too. Exercise restriction is advised for desmosomal gene mutation carriers due to exercise potentiating arrhythmias and heart failure.
  12. HCM patients with a sarcomeric pathogenic mutation have a worse outcome than genotype-negative patients. Penetrance, however, varies and clinical screening is warranted in genotype-positive individuals. Genetic testing in HCM also helps identify HCM phenocopies such as Fabry’s, amyloidosis, and RASopathies (Noonan’s syndrome).
  13. Certain types of nonischemic cardiomyopathy such as alcoholic, peripartum, and myocarditis can be genetically mediated with genes overlapping with DCM, HCM, and neuromuscular disease. Genetic testing should be considered in workup for these cardiomyopathies.
  14. Genetic testing can be obtained post-mortem also in individuals with sudden cardiac death at autopsy. It may also help guide in vitro fertilization when a family’s cause for cardiomyopathy is known. Embryos can be screened in vitro for the familial variant and those without the variant are implanted, averting cardiac risk in the offspring.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Exercise

Keywords: Amyloidosis, Arrhythmias, Cardiac, Bradycardia, Cardiomyopathies, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Connectin, Death, Sudden, Cardiac, Defibrillators, Implantable, Exercise, Fertilization in Vitro, Filamins, Genetic Counseling, Genetics, Genetic Testing, Heart Failure, Heterozygote, Hypertrophy, Lamin Type A, Mutation, Myocarditis, Neuromuscular Diseases, Peripartum Period, Primary Prevention, Risk Assessment, Sodium Channel Blockers

< Back to Listings