Marta Gigli1, Marco Merlo2, Sharon L Graw3, Giulia Barbati4, Teisha J Rowland3, Dobromir B Slavov3, Davide Stolfo2, Mary E Haywood3, Matteo Dal Ferro2, Alessandro Altinier2, Federica Ramani2, Francesca Brun2, Andrea Cocciolo1, Ilaria Puggia1, Gaetano Morea1, William J McKenna5, Francisco G La Rosa6, Matthew R G Taylor7, Gianfranco Sinagra2, Luisa Mestroni8. 1. Cardiovascular Department, Azienda Sanitaria-Universitaria Integrata Trieste "ASUITS," Trieste, Italy; Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 2. Cardiovascular Department, Azienda Sanitaria-Universitaria Integrata Trieste "ASUITS," Trieste, Italy. 3. Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 4. Biostatistics Unit, Department of Medical Sciences, University of Trieste, Trieste, Italy. 5. Institute of Cardiovascular Science, University College London, London, United Kingdom; Heart Hospital, Hamad Medical Corporation, Doha, Qatar. 6. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 7. Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: matthew.taylor@ucdenver.edu. 8. Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: Luisa.Mestroni@ucdenver.edu.
Abstract
BACKGROUND: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood. OBJECTIVES: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients. METHODS: A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF). RESULTS: A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction. CONCLUSIONS: Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
BACKGROUND: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood. OBJECTIVES: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients. METHODS: A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF). RESULTS: A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction. CONCLUSIONS: Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.
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