Author + information
- Received March 27, 2020
- Revision received June 14, 2020
- Accepted June 15, 2020
- Published online August 10, 2020.
- Jawan W. Abdulrahim, MDa,
- Lydia Coulter Kwee, PhDa,
- Fawaz Alenezi, MD, MScb,
- Albert Y. Sun, MDb,
- Aris Baras, MD, MBAc,
- Teminioluwa A. Ajayi, MD, MPHd,
- Ricardo Henao, PhDe,
- Christopher L. Holley, MD, PhDb,
- Robert W. McGarrah, MDa,b,
- James P. Daubert, MDb,
- Lauren K. Truby, MDb,
- Sreekanth Vemulapalli, MDb,
- Andrew Wang, MDb,
- Michel G. Khouri, MDb and
- Svati H. Shah, MD, MS, MHSa,b,∗ (, )@SvatiShah
- aDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina
- bDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- cRegeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, New York
- dDepartment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- eCenter for Applied Genomics and Precision Medicine, Duke University, Durham, North Carolina
- ↵∗Address for correspondence:
Dr. Svati H. Shah, Duke Molecular Physiology Institute, Duke University School of Medicine, 300 North Duke Street, Durham, North Carolina 27701.
Background Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed.
Objectives The purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort.
Methods Exomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease.
Results In total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals.
Conclusions Overall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a “missed opportunity,” which could be addressed by greater use of genetic testing of patients seen by cardiologists.
This work was supported by National Heart, Lung, and Blood Institute grant 5P01-HL036587 and Duke Forge Award-Duke CTSA grant UL1TR002553. Dr. Baras is an employee and stockholder of Regeneron Pharmaceuticals. Dr. Daubert has received honoraria for events committee, data safety monitoring board, consulting, advisory boards, or lectures from Abbott, Biosense, Biotronik, Boston Scientific, Microport, Farapulse, Medtronic, and Vytronus; and has received research grants from Abbott and Medtronic. Dr. Vemulapalli has received grants/contracts from the National Institutes of Health, Patient Centered Outcomes Research Institute, U.S. Food and Drug Administration (National Evaluation System for health Technology), Society of Thoracic Surgeons, American College of Cardiology, Boston Scientific, and Abbott Vascular; and has served as a consultant and/or on the advisory board for HeartFlow, Baylabs (Caption Health), Janssen, and Boston Scientific. Dr. Wang has served on the advisory board and as a consultant for Cytokinetics; has received an educational grant (to institution) from MyoKardia, Inc.; and has received research grants (to institution) from MyoKardia, Inc. and Cytokinetics. Dr. Shah has served as primary investigator of research sponsored agreement for Verily Life Sciences and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC author instructions page.
- Received March 27, 2020.
- Revision received June 14, 2020.
- Accepted June 15, 2020.
- 2020 American College of Cardiology Foundation
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