Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study.

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Citation: Circulation. 148(11):872-881, 2023 09 12.PMID: 37641966Institution: MedStar Heart & Vascular InstituteDepartment: MedStar Georgetown University Hospital/MedStar Washington Hospital Center | Plastic Surgery ResidencyForm of publication: Journal ArticleMedline article type(s): Clinical Study | Journal Article | Multicenter Study | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Cardiomyopathy, Dilated | *Precision Medicine | Adult | Aged | Black or African American | Black People | Cardiomyopathy, Dilated/eh [Ethnology] | Cardiomyopathy, Dilated/ep [Epidemiology] | Cardiomyopathy, Dilated/ge [Genetics] | Cardiomyopathy, Dilated/th [Therapy] | Defibrillators, Implantable | Drug Evaluation | Female | Humans | Male | Middle Aged | United States/ep [Epidemiology] | White | Year: 2023ISSN:
  • 0009-7322
Name of journal: CirculationAbstract: 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.CLINICALTRIALS: gov; Unique identifier: NCT03037632.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.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.REGISTRATION: URL: https://www.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.All authors: Hofmeyer M, Haas GJ, Jordan E, Cao J, Kransdorf E, Ewald GA, Morris AA, Owens A, Lowes B, Stoller D, Wilson Tang WH, Garg S, Trachtenberg BH, Shah P, Pamboukian SV, Sweitzer NK, Wheeler MT, Wilcox JE, Katz S, Pan S, Jimenez J, Smart F, Wang J, Gottlieb SS, Judge DP, Moore CK, Huggins GS, Kinnamon DD, Ni H, Hershberger REFiscal year: FY2024Digital Object Identifier: ORCID: Date added to catalog: 2023-11-22
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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.

CLINICALTRIALS: gov; Unique identifier: NCT03037632.

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.

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.

REGISTRATION: URL: https://www.

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.

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