Rare Truncating HAND2 Variants Predispose to Atrial Fibrillation.

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Atrial fibrillation (AF) is a prevalent arrhythmia affecting 1% of the global population, leading to severe complications like heart failure and stroke.
• Genetic factors are crucial in the pathogenesis of idiopathic AF, but genetic heterogeneity often obscures causative genes.
• Identifying genetic substrates for AF is essential for understanding its development and for personalized treatment strategies.

Purpose of the Study:

• To investigate the role of genetic variations in familial and idiopathic atrial fibrillation.
• To identify novel genes and mutations predisposing individuals to AF.
• To elucidate the functional consequences of identified genetic variants on AF-related gene expression.

Main Methods:

• A four-generation pedigree with familial AF and a cohort of 238 idiopathic AF patients were studied.
• Pan-exome sequencing and Sanger sequencing were employed to identify genetic variations.
• In vitro dual-reporter gene assays were used to assess the functional impact of HAND2 variants on gene transcription.

Main Results:

• Two novel heterozygous truncating HAND2 variations (p.(Trp46*) and p.(Gln113*)) were identified in AF patients and co-segregated with the phenotype.
• These HAND2 variants were absent in 266 healthy controls.
• Functional assays demonstrated that the mutant HAND2 proteins failed to activate AF-related genes (HCN4, NPPA) and impaired synergistic activation with GATA4.

Conclusions:

• HAND2 is identified as a significant candidate gene contributing to atrial fibrillation susceptibility.
• These findings reveal new insights into the molecular mechanisms underlying AF pathogenesis.
• The identified HAND2 variations offer potential molecular targets for the development of individualized AF therapies.