Coexistent HCN4 and GATA5 Rare Variants and Atrial Fibrillation in a Large Spanish Family

Background: Familial association of atrial fibrillation (AF) can involve single gene variants related to known arrhythmogenic mechanisms; however, genome-wide association studies often disclose complex genetic variants in familial and nonfamilial AF, making it difficult to relate to known pathogenetic mechanisms.

Methods: The finding of 4 siblings with AF led to studying 47 members of a family. Long-term Holter monitoring (average 298 hours) ruled out silent AF. Whole-exome sequencing was performed, and variants shared by the index cases were filtered and prioritised according to current recommendations. HCN4 currents (I_HCN4) were recorded in Chinese hamster ovary cells expressing human p.P1163H or native HCN4 channels with the use of the patch-clamp technique, and topologically associated domain analyses of GATA5 variant carriers were performed.

Results: The clinical study diagnosed 2 more AF cases. Five family members carried the heterozygous p.P1163H HCN4 variant, 14 carried the intronic 20,61040536,G,A GATA5 rare variant, and 9 carried both variants (HCN4+GATA5). Five of the 6 AF cases (onset age ranging from 33 to 70 years) carried both variants and 1 carried the GATA5 variant alone. Multivariate analysis showed that the presence of HCN4+GATA5 variants significantly increased AF risk (odds ratio 32.740, 95% confidence interval 1.812-591.408) independently from age, hypertension, and overweight. Functional testing showed that I_HCN4 generated by heterozygous p.P1163H were normal. Topologically associating domain analysis suggested that GATA5 could affect the expression of many genes, including those encoding microRNA-1.

Conclusion: The coincidence of 2 rare gene variants was independently associated with AF, but functional studies do not allow the postulation of the arrhythmogenic mechanisms involved.