Key result
Truncating PRRX1 variants appear in ~0.5% of sporadic AF patients and zero healthy controls.
Why the study?
Pathogenic variations in the PRRX1 gene have been shown to cause familial AF, but whether PRRX1 gene variations play a role in sporadic AF remained indefinite.
Case-Control (n=808)
This study provides initial evidence that haploinsufficient truncating variants in PRRX1 increase genetic susceptibility to sporadic atrial fibrillation by impairing transcriptional activation of SHOX2 and ISL1.
Answers are grounded in this paper and cite their sources.
PRRX1 truncating variants may contribute to sporadic AF; extends familial data but remains hypothesis-generating without practice change.
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.
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Li et al. (2026) conducted a case-control in Sporadic atrial fibrillation (n=808). Haploinsufficient truncating PRRX1 variants (Arg95 and Glu110) vs. Healthy volunteers without a family history of AF was evaluated on Presence of truncating PRRX1 variations. Heterozygous truncating PRRX1 variants (Arg95 and Glu110) were identified in 0.5% (2/398) of sporadic AF patients and 0% (0/410) of healthy controls.
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