Genetics of Adult-Onset Dilated Cardiomyopathy

Tayal U, Ware JS, Lakdawala NK, Heymans S, Prasad SK.
Understanding the Genetics of Adult-Onset Dilated Cardiomyopathy: What a Clinician Needs to Know. Eur Heart J 2021;42:2384-2396.

The following are key points to remember from this state-of-the-art review on the genetics of adult-onset dilated cardiomyopathy (DCM):

  1. DCM affects 1 in 250 people and is defined as left or biventricular dilatation and systolic dysfunction that is not explained by abnormal loading conditions or coronary artery disease.
  2. DCM is familial in 20-30% patients. About 40% of these families have an identifiable monogenic cause. However, genetic contribution to DCM risk does not always follow a Mendelian pattern and many variants with small effect sizes likely contribute to its inheritability with environmental factors acting as modifiers (for example, alcohol use). Hence, yield of genetic testing with DCM is still low.
  3. Monogenic DCM is usually autosomal dominant in inheritance. Currently, over 60 genes have been implicated affecting sarcomere, cytoskeleton, and desmosomal proteins. In addition, different variants in the same gene can cause a similar phenotype (i.e., allelic heterogeneity).
  4. Genetic variants in DCM also exhibit incomplete and age-related penetrance (i.e., the proportion of individuals with a particular genetic variant who develop the disease is age related). Typically, disease develops later, usually in middle age, or may not develop at all.
  5. There is also variable expressivity (i.e., heterogeneity in severity and diversity of illness for the same genetic abnormality). Accordingly, other modifiers such as the environment may be contributing to the phenotype.
  6. Currently, genetic testing is performed in individuals with DCM and this is known as confirmatory or diagnostic testing. This may help the patient or guide cascade testing in family members.
  7. Predictive testing is the use of a genetic test in an asymptomatic person to predict risk of disease in the future. Individuals who carry a familial variant but are unaffected are at risk but it is not possible to quantify the risk of developing overt disease at present. The European Society of Cardiology (ESC) guidelines recommend close clinical surveillance every 1-3 years and the American Heart Association guidelines recommend surveillance every 3-5 years. Other family members who do not carry the variant can be safely discharged from ongoing surveillance for DCM.
  8. Identifying a disease-causing variant in a prospective parent can be used to inform prenatal genetics such as pre-implantation genetic diagnosis, which involves in vitro fertilization with embryo selection of editing.
  9. At present, there is no consensus on when genetic testing should be performed for DCM patients. The American College of Medical Genetics and Genomics recommends genetic testing for patients with DCM for affected individuals and for family members at risk. The ESC recommends genetic testing for DCM patients when family members may benefit from a diagnosis or for diagnosis of a particular cardiomyopathy in the presence of features suggesting a specific etiology. The US and European Heart Rhythm Societies recommend genetic testing for DCM in the presence of significant conduction disease and/or a family history of sudden cardiac death.
  10. The authors of this review recommend that genetic testing for DCM has a higher yield than other screening investigations such as ferritin levels, and should be strongly considered in nonfamilial DCM, as well as 10-25% may have pathogenic variants.
  11. Prior to genetic testing, all individuals should have appropriate genetic counseling through a counselor or clinician with appropriate training and should involve providing information with psychosocial support. It is important to highlight that results may change in the future (i.e., a variant of uncertain significance [VUS] may be reclassified and that a negative test does not rule out a genetic cause). Family members should be counseled about variable expressivity and penetrance prior to genetic testing.
  12. In the European Union, discrimination with regard to health or life insurance on the basis of genetic features is prohibited. However, in the United States, health insurance providers cannot use genetic data to determine eligibility, but this is not true for life insurance. Accordingly, prior to genetic testing in an unaffected family member in United States, life insurance should be obtained.
  13. Results of a genetic test can be informative with a pathogenic variant identified or noninformative where either no variant is identified or a VUS is identified. A negative test does not rule out a genetic cause. A VUS cannot be used for cascade testing and may be reclassified in the future that can be identified using publicly available data sources such as ClinVar or gnomAD.
  14. Lamin variants causing DCM are frequently associated with conduction disease or atrial/ventricular tachyarrhythmia. Accordingly, guidelines recommend a primary prevention implantable cardioverter-defibrillator (ICD) be considered when a pacemaker is considered in a lamin patient. An ICD should also be considered in lamin patients with two of the following risk factors: ejection fraction <45%, nonsustained ventricular tachycardia, or male sex.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure

Keywords: Cardiomyopathies, Cardiomyopathy, Dilated, Coronary Artery Disease, Death, Sudden, Cardiac, Defibrillators, Implantable, Dilatation, Ferritins, Genetic Counseling, Genetic Testing, Genetics, Medical, Genomics, Heart Failure, Lamins, Pacemaker, Artificial, Patient Discharge, Primary Prevention, Social Support, Sarcomeres, Stroke Volume, Tachycardia, Ventricular

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