Haploinsufficient PRRX1 Variants Conferring Enhanced Susceptibility to Sporadic Atrial Fibrillation

Background/Objectives: Atrial fibrillation (AF), the most common type of clinical cardiac arrhythmia worldwide, leads to substantial human morbidity and mortality, and accumulating compelling evidence underscores genetic determinants underlying AF. Recent studies have demonstrated that pathogenic variations in the PRRX1 gene result in familial AF. Nevertheless, whether PRRX1 gene variations have a role in sporadic AF remains indefinite. Methods: A cohort of 398 subjects diagnosed with sporadic AF along with a group of 410 healthy volunteers without a family history of AF were enrolled prospectively. Sequencing exploration of PRRX1 was performed in all study participants. The functional characteristics of the uncovered PRRX1 variations were quantitatively assayed in HeLa cells using dual-reporter genes. Results: Two truncating PRRX1 variations in a heterozygous status, NM_022716.4: c.283C>T; p.(Arg95*) and NM_022716.4: c.328G>T; p.(Glu110*), were discovered in two of the 398 patients suffering from sporadic AF, respectively. Both variations were absent in the 820 control chromosomes. Biochemical measurements revealed that both Arg95* and Glu110* variants failed to transactivate SHOX2 and ISL1, two known genes causative for AF. Additionally, both variations ablated the synergistic activation of SHOX2 by PRRX1 and NKX2.5, another transcription factor causally linked to AF. Conclusions: The present research firstly indicates that haplo-insufficient PRRX1 variants increase genetic predisposition to sporadic AF, which adds new insight to the molecular etiopathogenesis of sporadic AF, highlighting the importance of population-specific genetic research for personalized medicine.