biostudies-literatureUnknownPavel MANCATS NIH HHSNHLBI NIH HHSRare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes, such as <i>TTN</i>, have also been implicated in AF pathogenesis, partly through the development of atrial myopathy; however, the underlying mechanisms are poorly understood. While <i>TTN</i> truncating variants (<i>TTN</i>tvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear. We show that rare <i>TTNmvs</i> are associated with worse clinical outcomes in a single-center ethnic minority clinical cohort and uncover a pathogenic mechanism by which the T32756I variant drives AF. Modeling the <i>TTN</i>-T32756I varimedRxiv : the preprint server for health sciences2024.12.06.24318402https://www.ebi.ac.uk/biostudies/studies/S-EPMC11643245biostudies-literatureA titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation.PMC11643245T32 HL139439UL1 TR002003R01 HL148444R01 HL150586Owais AOrnelas-Loredo ADarbar DChen HBarney MSandu SDeSantiago JBaskaran AAl-Azzam BSridhar ADarbar FARehman JHill MChalazan BPavel MAfalseA titin missense variant drives atrial electrical remodeling and is associated with atrial fibrillation.Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes, such as <i>TTN</i>, have also been implicated in AF pathogenesis, partly through the development of atrial myopathy; however, the underlying mechanisms are poorly understood. While <i>TTN</i> truncating variants (<i>TTN</i>tvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear. We show that rare <i>TTNmvs</i> are associated with worse clinical outcomes in a single-center ethnic minority clinical cohort and uncover a pathogenic mechanism by which the T32756I variant drives AF. Modeling the <i>TTN</i>-T32756I vari2025-01-01T00:00:00Z2025 Nov2026-07-03T03:23:35.388Z2025-04-04T20:27:56.757ZS-EPMC116432453967742410.1101/2024.12.06.24318402