Deep sequencing of atrial fibrillation patients with mitral
valve regurgitation shows no evidence of mosaicism but
reveals novel rare germline variants
Q2
Emilie Gregers, MD,*
†‡
Gustav Ahlberg, MSc,*
†‡
Thea Christensen, MSc,*
x
Javad Jabbari, MSc, PhD,*
†‡
Kirstine O. Larsen, BSc,*
x
Cecilie B. Herfelt, MSc,*
†‡
Kristoffer M. Henningsen, MD, PhD,*
†‡
Laura Andreasen, MD,*
†‡
Jens J. Thiis, MD,
{
Jens Lund, MD,
{
Susanne Holme, MD,
{
Stig Haunsø, MD, DMSc,*
†‡
Bo H. Bentzen, MSc, PhD,*
x
Nicole Schmitt, MSc, PhD,*
x
Jesper H. Svendsen, MD, DMSc, FESC,*
†‡
Morten S. Olesen, MSc, PhD*
†‡
Q1
From the *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,
x
Department of Biomedical Science,
University of Copenhagen, Copenhagen, Denmark, and
{
Department of Cardiothoracic Surgery,
Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
BACKGROUND Atrial fibrillation (AF) is the most common cardiac
arrhythmia. Valvular heart disease is a strong predictor, yet the un-
derlying molecular mechanisms are unknown.
OBJECTIVE The purpose of this study was to investigate the preva-
lence of somatic variants in AF candidate genes in an AF patient pop-
ulation 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 Sys-
tem. MuTect software was used for identification of somatic point
variants. We functionally characterized selected variants using elec-
trophysiologic 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 predic-
tions. We identified rare variants in genes never directly associated
with AF: KCNE4, SCN4B, NEURL1, and CAND2. Interestingly, 7 pa-
tients (16%) had variants in genes involved in cellular potassium
handling. The variants KCNQ1 (p.G272S) and KCNH2 (p.A913V) re-
sulted 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 un-
known factors in the pathogenesis of AF.
KEYWORDS Atrial fibrillation; Genetics; Bioinformatics; Cardiac tis-
sue; Mitral valve regurgitation; Somatic mutations; Somatic variants
(Heart Rhythm 2017;-:1–8)
©
2017 Heart Rhythm Society.
All rights reserved.
Introduction
Atrial fibrillation (AF) is a supraventricular cardiac
arrhythmia characterized by chaotic contractions of the atria.
The mechanism of AF initiation is not fully understood,
although it is generally agreed that rapid atrial activation
from or near the pulmonary veins (PVs) plays an important
role.
1
Moreover, a combination of PV triggering, autonomic
innervation by atrial ganglion plexi, and rotors located in
the atria might be responsible for maintenance of AF.
2
Several
adverse events are related to AF, including stroke, heart fail-
ure, reduced quality of life, and increased mortality.
3
AF is the
most common clinically significant cardiac arrhythmia, with
This work was made possible by grants from The Research foundation of
the Heart Centre Rigshospitalet; The Danish Heart Foundation (Grant 11-04-
R84-A3401-22654); The Danish National Research Foundation Centre for
Cardiac Arrhythmia; The John and Birthe Meyer Foundation; the A.P. Møller
Foundation for the Advancement of Medical Science; The Foundation of 17-
12-1981, Direktør Ib Henriksens fond; The Arvid Nilsson Foundation; The
Lundbeck Foundation; The Danielsen Foundation; and Fondsbørsvekslerer
Henry Hansen og Hustru Karla Hansen, født Westergaards, Legat. Dr. Gregers,
G, Ahlberg, and Dr. Jabbari authors contributed equally to the work. Drs.
Svendsen and Olesen contributed equally to the work. Address reprint re-
quests and correspondence: Dr. Jesper Hastrup Svendsen, Department of
Cardiology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark.
E-mail address: jesper.hastrup.svendsen@regionh.dk.
1547-5271/$-see front matter © 2017 Heart Rhythm Society. All rights reserved. http://dx.doi.org/10.1016/j.hrthm.2017.05.027
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