Rare Truncating HAND2 Variants Predispose to Atrial Fibrillation

Background/Objectives: As the most prevalent supraventricular arrhythmia, affecting around 1% of people worldwide, atrial fibrillation (AF) is implicated with a multitude of detrimental clinical sequelae, encompassing congestive failure, thromboembolic cerebral stroke, and premature death. Accumulating epidemiological evidence convincingly demonstrates genetic defects as a cornerstone in the pathogenesis of idiopathic AF. Despite significant genetic underpinnings responsible for AF, owing to substantial genetic heterogeneity, the predisposing genetic substrates for AF in most individuals remain to be ascertained. Methods: A four-generation pedigree suffering from familial AF and a cohort of 238 subjects affected with idiopathic AF, together with 266 healthy people, were enrolled prospectively. Pan-exome sequencing analysis was implemented on the chosen AF pedigree members, and Sanger sequencing assay was performed on all research subjects. The functional effects of the detected HAND2 variations were examined via an in vitro dual-reporter gene measurement. Results: Two novel heterozygous truncating HAND2 variations, NM_021973.3: c.138G>A; p.(Trp46*) and NM_021973.3: c.337C>T; p.(Gln113*), were discovered in the AF pedigree and one of the 238 AF cases, respectively. The two HAND2 variants co-segregated with the AF phenotype and were absent from the 532 control chromosomes of 266 healthy individuals. Quantitative reporter gene assays unveiled that both Trp46*- and Gln113*-mutant HAND2 failed to transcriptionally activate HCN4 and NPPA, two AF-causative genes. Additionally, the two variations nullified the synergistic transcriptional activation of NPPA by HAND2 and GATA4, another recognized gene predisposing to AF. Conclusions: These findings support HAND2 as a strong candidate gene contributing to AF susceptibility, which unravels novel etiopathogenesis underpinning the occurrence and perpetuation of AF and offers a potential molecular target for individualized medicine.