Effect of Occurrence of Lamin A/C (LMNA) Genetic Variants in a Cohort of 101 Consecutive Apparent “Lone AF” Patients: Results and Insights

Abstract

ObjectiveMutations in the Lamin A/C(LMNA) gene are commonly associated with cardiac manifestations, such as dilated cardiomyopathy (DCM) and conduction system disease. However, the overall spectrum and penetrance of rare LMNA variants are unknown. The present study described the presence of LMNAvariants in patients with “lone atrial fibrillation (AF)” as their sole clinical presentation.MethodsOne-hundred and one consecutive patients with “lone AF” criteria were initially screened by genetic testing. Genetic variants were classified according to the American College of Genetic and Genomic criteria. All subjects were evaluated through clinical and familial history, ECG, 24-h Holter monitoring, echocardiogram, cardiac magnetic resonance, treatment response, and the present relatives of LMNA carriers. In addition, whole-exome data from 49,960 UK Biobank (UKB) participants were analyzed to describe the overall penetrance of rare LMNA missense and loss of function (LOF) variants.ResultsThree missense variants in LMNA were identified in probands with AF as their first and unique clinical manifestation. Other five first-degree relatives, after the screening, also presented LMNA gene variants. Among 49,960 analyzed UKB participants, 331 carried rare LMNA missense or LOF variant. Participants who carried a rare LMNA variant were significantly associated with higher odds of arrhythmic events and of an abnormal ECG in the per-protocol ECG exam (p = 0.03 and p = 0.05, respectively).ConclusionAlthough a rare occurrence, our findings emphasize the possibility of an initial presentation of apparently “lone AF” in LMNA gene variant carriers.

Troponin T Assessment Allows for Identification of Mutation Carriers among Young Relatives of Patients with LMNA-Related Dilated Cardiomyopathy

“…The aftermath of prolonged cardiomyocyte injury is non-specific replacement fibrosis, as seen in endomyocardial biopsy or as late gadolinium enhancement in the CMR study [ 23 , 24 , 25 ]. Consequently, myocardial fibrosis is considered to be responsible for the development of electrical instability, leading to arrhythmia [ 6 , 26 , 27 , 28 , 29 , 30 , 31 ], and, over time, to mechanical impairment.…”

2024 European Heart Rhythm Association/Heart Rhythm Society/Asia Pacific Heart Rhythm Society/Latin American Heart Rhythm Society expert consensus statement on catheter and surgical ablation of atrial fibrillation

“…The first rare pathogenic variant linked to familial AF was found in the Kv1.7 voltage-gated potassium channel. 41 Since then, further variants have been identified in genes encoding potassium channels, 42–48 sodium channel, 49–51 and other non-channel proteins 52 , 53 in patients and families with AF. In addition, genome-wide association studies comparing AF patients with the general population have associated a common variant at the 4q25 locus, a non-coding region of the genome near the gene PITX2, with a 60% increased risk of developing AF.…”

Ion channel dysfunction and fibrosis in atrial fibrillation: Two sides of the same coin

“…4 Finally, mutations in LMNA gene (encoding Lamin A/C) have been linked to AF. 75,76 These proteins play a key role in nuclear architecture maintenance, chromatin organization, and gene expression regulation 77 ; their alteration causes myocardial fibrosis via aberrant TGF-β1 signaling 78,79 and predisposes the patient to development of both electrical instability and mechanical impairment. 80 Of note reported a prevalence of AF is as high as 61% in patients phenotypically affected by dilated cardiomyopathy (DCM) with LMNA gene mutations.…”