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Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study
Mark Hofmeyer1, Garrie J Haas2,3,4, Elizabeth Jordan2,5
1MedStar Health Research Institute, Medstar Washington Hospital Center, Washington, DC (M.H.).
Insights
Advanced dilated cardiomyopathy (DCM) is linked to a higher likelihood of rare genetic variants. This discovery aids in assessing outcomes for DCM patients and their families.
Area of Science:
- Cardiovascular Genetics
- Precision Medicine
- Genomic Medicine
Background:
- Dilated cardiomyopathy (DCM) is a genetic heart condition.
- Advanced DCM necessitates advanced treatments like left ventricular assist devices (LVAD) or heart transplantation (HT).
- The genetic basis of DCM is known, but its link to advanced disease stages remains understudied.
Purpose of the Study:
- To investigate the association between rare genetic variants and advanced dilated cardiomyopathy (DCM).
- To analyze genetic data in a diverse cohort to understand DCM severity.
- To identify potential genetic risk factors for advanced DCM requiring LVAD/HT.
Main Methods:
- Analyzed clinical and genetic data from 1198 patients in the US DCM Precision Medicine Study (2016-2021).
- Classified DCM severity into advanced (LVAD/HT), moderate (ICD only), and mild (neither).
- Assessed rare variants in 36 DCM genes, controlling for demographic, lifestyle, and comorbidity factors.
Main Results:
- 26.2% of patients with LVAD/HT had pathogenic/likely pathogenic variants, versus 15.9% (ICD only) and 15.0% (neither).
- Advanced DCM patients were more likely to have pathogenic/likely pathogenic rare variants (OR 2.3; 95% CI, 1.5-3.6) after adjustment.
- Genetic findings did not differ significantly by ancestry or between ICD-only and no-device groups.
Conclusions:
- Advanced DCM is associated with a higher prevalence of pathogenic/likely pathogenic rare variants in DCM genes.
- These genetic findings may improve risk stratification for DCM patients.
- Understanding genetic links can aid management strategies for DCM patients and their families.
Background:
Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied.
Methods:
We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link.
Results:
Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD.
Conclusions:
Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members.
Registration:
URL: https://www.
Clinicaltrials:
gov; Unique identifier: NCT03037632.
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