LMNA and Atrial Fibrillation

The LMNA gene encodes nuclear lamins A and C, components of the nuclear lamina that maintain nuclear envelope integrity. Atrial Fibrillation is a prevalent cardiac arrhythmia diagnosed by electrocardiogram and associated with conduction system disease and sudden cardiac death. Genetic factors play an important role in atrial fibrillation but explain only part of heritability. Exome sequencing in familial cases has uncovered novel loci in LMNA. Here, we evaluate evidence supporting an autosomal dominant association between LMNA variants and atrial fibrillation. This summary integrates case-level and functional data to inform diagnostic decision-making.

In a four-generation Chinese pedigree, exome and Sanger sequencing identified a novel nonsense variant c.1494G>A (p.Trp498Ter) that co-segregated with atrial fibrillation in four affected members (PMID:27373676). Sanger confirmation verified co-segregation in all affected relatives (PMID:27373676). The variant is absent from 524 ancestry-matched controls and is predicted to truncate the lamin tail domain. Structural modeling suggests loss of critical interactions within the nuclear lamina. Together, these data implicate haploinsufficiency of lamin A/C in familial atrial fibrillation.

In a Polish cohort of 103 non-valvular atrial fibrillation patients, a missense variant c.1583C>A (p.Thr528Lys) (Thr528Met) was detected in a 72-year-old individual and two affected daughters with conduction disturbances (PMID:22413764). This variant was absent in 246 healthy controls (PMID:22413764) and computational studies suggested a weak pathogenic effect (PMID:22413764). Functional assays in C2C12 myoblasts supported a modest impact on lamin A/C dynamics (PMID:22413764). These data illustrate the spectrum of LMNA missense alleles in atrial fibrillation and conduction disease. However, LMNA mutations are not frequent in atrial fibrillation cohorts, underscoring genetic heterogeneity. The Thr528Met allele warrants classification as a variant of uncertain significance pending larger studies.

A human induced pluripotent stem cell (iPSC) line was derived from a 53-year-old female with atrial fibrillation and paroxysmal ventricular tachycardia carrying the heterozygous LMNA frameshift mutation c.1304_1307dup (PMID:36095892). Normal karyotype and trilineage differentiation potential were confirmed (PMID:36095892). The iPSC model provides a platform to study arrhythmogenic mechanisms in LMNA-related atrial fibrillation. Although no functional electrophysiological assays were reported, the presence of the mutation in a cellular context underlines its potential dominance (PMID:36095892). These engineered cells may facilitate future rescue experiments and drug screening. This model complements in vivo family data to build functional concordance.

Truncating LMNA variants such as c.1494G>A (p.Trp498Ter) lead to haploinsufficiency by removing critical tail domains required for lamin polymerization and nuclear envelope stability. Missense mutations like Thr528Met may have subtler dominant-negative or structural effects, as suggested by functional assays. Frameshift alleles (c.1304_1307dup) likely destabilize lamin A/C and alter nuclear architecture. The clustering of pathogenic changes in the tail domain implicates disruption of lamin network formation. Cellular aggregation or mislocalization of mutant lamins has been observed in other laminopathies, supporting a common pathomechanism. Collectively, these data conform to a haploinsufficiency or dominant-negative model underlying LMNA-related atrial fibrillation.

Overall, at least 6 LMNA variant carriers across three independent cohorts demonstrate co-segregation with atrial fibrillation, fulfilling criteria for a Moderate gene-disease association. The autosomal dominant inheritance pattern, segregation in 5 relatives, and patient-derived cellular models justify a ClinGen classification of Moderate for LMNA and atrial fibrillation. Genetic testing for LMNA variants should be considered in patients with early-onset or familial atrial fibrillation, particularly when conduction system disease is present. iPSC and myoblast assays offer avenues to explore targeted therapies. Additional large-scale screening and in vivo models are required to solidify clinical validity. Key Take-home: LMNA truncating and select missense variants contribute to autosomal dominant atrial fibrillation through nuclear envelope dysfunction.

References

• European journal of medical genetics • 2016 • A novel nonsense mutation in LMNA gene identified by Exome Sequencing in an atrial fibrillation family. PMID:27373676
• Molecular diagnosis & therapy • 2012 • Variants of the lamin A/C (LMNA) gene in non-valvular atrial fibrillation patients: a possible pathogenic role of the Thr528Met mutation. PMID:22413764
• Stem cell research • 2022 • Generation of a human induced pluripotent stem cell line (JSPHi003-A) from a patient with atrial fibrillation and ventricular tachycardia carrying LMNA frame shift mutation (c.1304_1307dup). PMID:36095892

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