title: Targeted deep sequencing reveals no definitive evidence for somatic mosaicism in atrial fibrillation.
abstract: BACKGROUND
  Studies of ≤15 atrial fibrillation (AF) patients have identified atrial-specific mutations within connexin genes, suggesting that somatic mutations may account for sporadic cases of the arrhythmia. We sought to identify atrial somatic mutations among patients with and without AF using targeted deep next-generation sequencing of 560 genes, including genetic culprits implicated in AF, the Mendelian cardiomyopathies and channelopathies, and all ion channels within the genome.
  
  
  RESULTS
  Targeted gene capture and next-generation sequencing were performed on DNA from lymphocytes and left atrial appendages of 34 patients (25 with AF). Twenty AF patients had undergone cardiac surgery exclusively for pulmonary vein isolation and 17 had no structural heart disease. Sequence alignment and variant calling were performed for each atrial-lymphocyte pair using the Burrows-Wheeler Aligner, the Genome Analysis Toolkit, and MuTect packages. Next-generation sequencing yielded a median 265-fold coverage depth (interquartile range, 64-369). Comparison of the 3 million base pairs from each atrial-lymphocyte pair revealed a single potential somatic missense mutation in 3 AF patients and 2 in a single control (12 versus 11%; P=1). All potential discordant variants had low allelic fractions (range, 2.3%-7.3%) and none were detected with conventional sequencing.
  
  
  CONCLUSIONS
  Using high-depth next-generation sequencing and state-of-the art somatic mutation calling approaches, no pathogenic atrial somatic mutations could be confirmed among 25 AF patients in a comprehensive cardiac arrhythmia genetic panel. These findings indicate that atrial-specific mutations are rare and that somatic mosaicism is unlikely to exert a prominent role in AF pathogenesis.
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.).
authors.forename: Jason D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.).
authors.forename: James
authors.initials: J
authors.lastname: Longoria
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.).
authors.forename: Annie
authors.initials: A
authors.lastname: Poon
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.).
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.).
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dewland
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.).
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.).
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Olgin
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.). marcusg@medicine.ucsf.edu rahul.deo@ucsf.edu.
authors.forename: Rahul C
authors.initials: RC
authors.lastname: Deo
authors.affiliation: From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Cardiovascular Research Institute (A.P., P.-Y.K., R.C.D.), and Department of Medicine, California Institute for Quantitative Biosciences, Institute for Human Genetics (R.C.D.), University of California San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); and Arrhythmia Research Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (M.H.G.). marcusg@medicine.ucsf.edu rahul.deo@ucsf.edu.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Marcus
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics*; D005260:Female; D006325:Heart Atria; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008214:Lymphocytes; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D020125:Mutation, Missense
keywords: arrhythmias, cardiac; atrial fibrillation; cardiac electrophysiology; computational biology; genetics; mosaicism