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

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. 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 (IHCN4) 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 associating domain analyses of GATA5 variant were performed. 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 32.7, 95% confidence interval 1.8-591.4) independently from age, hypertension, and overweight. Functional testing showed that IHCN4 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. 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. L'association familiale de la fibrillation auriculaire (FA) peut impliquer des variants d'un seul gène liés à des mécanismes arythmogènes connus; cependant, les études d'association pangénomique révèlent souvent des variants génétiques complexes dans la FA familiale et non familiale, rendant difficile l'établissement d'un lien avec les mécanismes pathogéniques connus. La découverte de 4 frères et sœurs atteints de FA a conduit à l'étude de 47 membres d'une même famille. Un suivi long terme par Holter (moyenne de 298 heures) a permis d'exclure la présence d'une FA silencieuse. Un séquençage de l'exome entier a été réalisé, et les variants partagés par les cas index ont été filtrés et priorisés selon les recomman