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Rare Variant Genetics and Dilated Cardiomyopathy Severity
Quick Takes
- Patients with advanced dilated cardiomyopathy (DCM) requiring LVAD or heart transplant were twice as likely to have pathogenic or likely pathogenic genetic variants when compared to patients not requiring LVAD or heart transplant. This association did not differ between those of African or European genomic ancestry.
- Pathogenic or likely pathogenic variants were noted in 26.2% of patients with advanced DCM, which has significant implications for the number of family members that are recommended for genetic screening.
Study Questions:
What is the association between rare variant genetics in dilated cardiomyopathy (DCM) and disease severity, with severity of disease defined as requiring a left ventricular assist device (LVAD) or heart transplant (HT), implantable cardioverter-defibrillator (ICD) only, or neither (no LVAD/HT/ICD)?
Methods:
This was an analysis of the DCM Precision Medicine Study, which enrolled a diverse cohort of participants from 25 US sites between 2016 and 2021. The initial study recruited patients with DCM (probands) and relatives of these patients. This analysis examined the 1,198 eligible patients meeting diagnostic criteria for DCM with complete genotyping data. These patients were divided into three disease severity groups: advanced DCM requiring LVAD or HT (LVAD/HT group), nonadvanced DCM but requiring ICD only (ICD group), or nonadvanced DCM without ICD or LVAD/HT (no LVAD/HT/ICD group). A panel of 36 clinically relevant DCM genes were assessed. Rare variants in these genes were classified as pathogenic or likely pathogenic (P/LP), or variants of uncertain significance (VUS). The association between DCM severity and rare variant genetic findings was assessed.
Results:
Patients included in this analysis were a mean (standard deviation) age of 51.9 (13.6) years, with 44% being female, 42% of African ancestry, and 56% of European ancestry (continental ancestry determined by highest proportion of genomic ancestry). There were 347 patients in the LVAD/HT group, 511 in the ICD group, and 340 in the no LVAD/HT/ICD group. In the overall cohort, 223 patients (18.6%) carried P/LP variants and 515 (43.0%) had a VUS. P/LP variants were found in 26.2%, 15.9%, and 15.0% of the LVAD/HT, ICD, and no LVAD/HT/ICD groups, respectively. After adjusting for sociodemographic characteristics and comorbidities, patients with DCM in the LVAD/HT group compared to the no LVAD/HT/ICD group were more likely to have P/LP DCM variants (odds ratio, 2.3; 95% confidence interval, 1.5-3.6). This finding did not differ by ancestry. Rates of rare variants were similar between the ICD group and the no LVAD/HT/ICD group.
Conclusions:
Advanced DCM requiring LVAD or HT was associated with higher odds of having P/LP rare variants in DCM genes when compared to nonadvanced DCM (not requiring LVAD, HT, or ICD).
Perspective:
It is often difficult to predict which patients with DCM are more likely to have worse outcomes, especially at the time of diagnosis or early in the disease course. The role of genetic testing to predict outcomes has been understudied. This large, multicenter study, with broad representation of African and European genomic ancestry, highlights the potential role for genetic testing in helping to risk stratify patients, demonstrating that those with advanced DCM were over two times as likely to have a P/LP genetic variant compared to nonadvanced DCM. This suggests a potential role for more broad genetic testing to provide prognostic information. Also, given that 26.2% of patients with advanced DCM have a P/LP variant, this has implications for family members, as genetic screening of first-degree relatives is recommended. Early identification of family members at risk for DCM may have an important impact on future outcomes.
Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Heart Transplant, Mechanical Circulatory Support
Keywords: Cardiomyopathy, Dilated, Defibrillators, Implantable, Genetics, Heart-Assist Devices, Heart Transplantation
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