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Heart Rhythm. 2017 Feb;14(2):284-291. doi: 10.1016/j.hrthm.2016.10.014. Epub 2016 Oct 15.

Gain-of-function mutations in GATA6 lead to atrial fibrillation.

Author information

Cardiovascular Research Center and.
Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, Massachusetts; Preventive Medicine and Cardiovascular Medicine Sections, Department of Medicine; Cardiology Division, Department of Medicine.
Cardiovascular Research Center and; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts.
Computational Biomedicine Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
Cardiovascular Research Center and; Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:



The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood.


We sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects.


We evaluated a pedigree with 16 family members, 1 with an atrial septal defect, 1 with a ventricular septal defect, and 3 with AF; we performed whole exome sequencing in 3 affected family members. Given that early-onset AF was prominent in the family, we then screened individuals with early-onset AF, defined as an age of onset <66 years, for mutations in GATA6. Variants were functionally characterized using reporter assays in a mammalian cell line.


Exome sequencing in 3 affected individuals identified a conserved mutation, R585L, in the transcription factor gene GATA6. In the Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study, the mean age of AF onset was 47.1 ± 10.9 years; 79% of the participants were men; and there was no evidence of structural heart disease. We identified 3 GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, we found that 3 of the 4 variants had a marked upregulation of luciferase activity (R585L: 4.1-fold, P < .0001; P91S: 2.5-fold, P = .0002; A177T; 1.7-fold, P = .03). In addition, when co-overexpressed with GATA4 and MEF2C, GATA6 variants exhibited upregulation of the alpha myosin heavy chain and atrial natriuretic peptide reporter activity.


Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in a family with sporadic, early-onset AF.


Atrial fibrillation; Genetics; Mutation; Transcription factor

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