Emilie Gregers1, Gustav Ahlberg1, Thea Christensen2, Javad Jabbari1, Kirstine O Larsen2, Cecilie B Herfelt1, Kristoffer M Henningsen1, Laura Andreasen1, Jens J Thiis3, Jens Lund3, Susanne Holme3, Stig Haunsø1, Bo H Bentzen2, Nicole Schmitt2, Jesper H Svendsen4, Morten S Olesen1. 1. Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 2. Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark; Department of Biomedical Science, University of Copenhagen, Copenhagen, Denmark. 3. Department of Cardiothoracic Surgery, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 4. Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark; Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: jesper.hastrup.svendsen@regionh.dk.
Abstract
BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Valvular heart disease is a strong predictor, yet the underlying molecular mechanisms are unknown. OBJECTIVE: The purpose of this study was to investigate the prevalence of somatic variants in AF candidate genes in an AF patient population undergoing surgery for mitral valve regurgitation (MVR) to determine whether these patients are genetically predisposed to AF. METHODS: DNA was extracted from blood and left atrial tissue from 44 AF patients with MVR. Using next-generation sequencing, we investigated 110 genes using the HaloPlex Target Enrichment System. MuTect software was used for identification of somatic point variants. We functionally characterized selected variants using electrophysiologic techniques. RESULTS: No somatic variants were identified in the cardiac tissue. Thirty-three patients (75%) had a rare germline variation in ≥1 candidate genes. Fourteen variants were novel. Fifteen variants were predicted damaging or likely damaging in ≥6 in silico predictions. We identified rare variants in genes never directly associated with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 patients (16%) had variants in genes involved in cellular potassium handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) resulted in gain of function due to faster activation (KCNQ1) and slowed deactivation kinetics (KCNQ1, KCNH2). CONCLUSION: We did not find any somatic variants in patients with AF and MVR. Surprisingly, we found that our cohort of non-lone AF patients might, like lone AF patients, be predisposed to AF by rare germline variants. Our findings emphasize the extent of still unknown factors in the pathogenesis of AF.
BACKGROUND:Atrial fibrillation (AF) is the most common cardiac arrhythmia. Valvular heart disease is a strong predictor, yet the underlying molecular mechanisms are unknown. OBJECTIVE: The purpose of this study was to investigate the prevalence of somatic variants in AF candidate genes in an AFpatient population undergoing surgery for mitral valve regurgitation (MVR) to determine whether these patients are genetically predisposed to AF. METHODS: DNA was extracted from blood and left atrial tissue from 44 AFpatients with MVR. Using next-generation sequencing, we investigated 110 genes using the HaloPlex Target Enrichment System. MuTect software was used for identification of somatic point variants. We functionally characterized selected variants using electrophysiologic techniques. RESULTS: No somatic variants were identified in the cardiac tissue. Thirty-three patients (75%) had a rare germline variation in ≥1 candidate genes. Fourteen variants were novel. Fifteen variants were predicted damaging or likely damaging in ≥6 in silico predictions. We identified rare variants in genes never directly associated with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 patients (16%) had variants in genes involved in cellular potassium handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) resulted in gain of function due to faster activation (KCNQ1) and slowed deactivation kinetics (KCNQ1, KCNH2). CONCLUSION: We did not find any somatic variants in patients with AF and MVR. Surprisingly, we found that our cohort of non-lone AFpatients might, like lone AFpatients, be predisposed to AF by rare germline variants. Our findings emphasize the extent of still unknown factors in the pathogenesis of AF.
Authors: Agnieszka A Górska; Clara Sandmann; Eva Riechert; Christoph Hofmann; Ellen Malovrh; Eshita Varma; Vivien Kmietczyk; Julie Ölschläger; Lonny Jürgensen; Verena Kamuf-Schenk; Claudia Stroh; Jennifer Furkel; Mathias H Konstandin; Carsten Sticht; Etienne Boileau; Christoph Dieterich; Norbert Frey; Hugo A Katus; Shirin Doroudgar; Mirko Völkers Journal: EMBO Rep Date: 2021-10-04 Impact factor: 8.807