Ravi A Shah1, Babken Asatryan2, Ghaith Sharaf Dabbagh3,4, Nay Aung5,6, Mohammed Y Khanji5,6, Luis R Lopes7, Stefan van Duijvenboden6, Anthony Holmes8, Daniele Muser9, Andrew P Landstrom10, Aaron Mark Lee6, Pankaj Arora11, Christopher Semsarian12,13,14, Virend K Somers15, Anjali T Owens16, Patricia B Munroe6, Steffen E Petersen6, C Anwar A Chahal3,9,15. 1. Imperial College Healthcare NHS Trust, London, United Kingdom (R.A.S.). 2. Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (B.A.). 3. Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, PA (G.S.D., C.A.A.C.). 4. University of Michigan, Division of Cardiovascular Medicine, Ann Arbor (G.S.D.). 5. Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom (N.A., M.Y.K., L.R.L., A.M.L., S.E.P., C.A.A.C.). 6. NIHR Barts Biomedical Research Centre, William Harvey Research Institute, Queen Mary University of London, United Kingdom (N.A., M.Y.K., S.v.D., A.M.L., P.B.M., S.E.P.). 7. Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom (L.R.L.). 8. GE Healthcare, Chicago, IL (A.H.). 9. Cardiac Electrophysiology, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia (D.M., C.A.A.C.). 10. Departments of Pediatrics, Division of Cardiology, and Cell Biology, Duke University School of Medicine, Durham, NC (A.P.L.). 11. Division of Cardiovascular Disease, University of Alabama at Birmingham (P.A.). 12. Agnes Ginges Centre for Molecular Cardiology at Centenary Institute (C.S.), The University of Sydney, New South Wales, Australia. 13. Sydney Medical School Faculty of Medicine and Health (C.S.), The University of Sydney, New South Wales, Australia. 14. Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.S.). 15. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (V.K.S., C.A.A.C.). 16. Center for Inherited Cardiovascular Disease, Cardiovascular Division, University of Pennsylvania Perelman School of Medicine, Philadelphia (A.T.O.).
Abstract
BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. METHODS: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. RESULTS: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. CONCLUSIONS: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.
BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. METHODS: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. RESULTS: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. CONCLUSIONS: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.
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