Gain of function mutations in GATA6 lead to atrial fibrillation

Background The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood. Objective We sought to determine the causative mutation in a family with AF, atrial septal and ventricular septal defects. Methods We evaluated a pedigree with 16 family members, one with an atrial septal defect, one with a ventricular septal defect and three with AF; we performed whole exome sequencing in three 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. Results Exome sequencing in three affected individuals identified a conserved mutation, R585L, in the transcription factor gene, GATA6 . In the MGH AF Study the mean age of AF onset was 47.1 ± 10.9 years, 79% of the participants were male, and there was no evidence of structural heart disease. We identified three GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving NPPA promoter reporter, we found that three of the four variants had a marked upregulation of luciferase activity (R585L; 4.1 fold, p