Highlight
Missense versus truncating LMNA variants differentially affect arrhythmic risk: truncating variants were associated with a 72% higher risk of malignant ventricular arrhythmia (VA) than missense variants. Among missense carriers, variants in the lamin A/C tail domain and in exons 7–12 were associated with substantially lower VA risk.
Background
LMNA encodes the nuclear envelope proteins lamin A and C and is a well-established cause of familial dilated cardiomyopathy with prominent electrical disease (conduction system disease and malignant ventricular arrhythmia). LMNA cardiomyopathy is characterized by an elevated lifetime risk of sudden cardiac death and progressive heart failure, often prompting early consideration of implantable cardioverter-defibrillator (ICD) therapy even when left ventricular ejection fraction (LVEF) is preserved.
Historically, genotype has been used qualitatively in risk stratification: truncating (nonsense, frameshift, canonical splice-site) LMNA variants were associated with worse outcomes than missense variants, but the contribution of variant position within the protein (head, rod, tail domains) and within the gene (exon-level) to clinical risk has been poorly defined. A clearer understanding of how both variant type and spatial distribution influence outcomes could refine individualized counseling and device decision-making.
Study design
This international, multicenter retrospective cohort study combined an LMNA registry (from January 2013 onward) and tertiary cardiomyopathy center datasets (January 2000–June 2017) to evaluate the association of LMNA variant type and position with cardiac outcomes. Inclusion criteria were carriers of pathogenic or likely pathogenic LMNA variants without prior malignant VA at baseline. The primary outcome was time to malignant VA (sudden cardiac death, appropriate ICD therapy, or hemodynamically unstable ventricular arrhythmia). The secondary outcome was a composite of advanced heart failure (nonsudden cardiac death, left ventricular assist device implantation, or heart transplant).
Patients were categorized by variant type (missense vs truncating), by affected protein domain (head, rod, tail), and by gene region (notably exons 7–12). Multivariable Cox proportional hazards models were used to adjust for relevant clinical covariables. Data analysis spanned March 2022 to March 2025.
Key findings
Population and follow-up
– Total N = 718 pathogenic/likely pathogenic LMNA variant carriers.
– Mean age 41.1 years (SD 14.3); 53.1% female.
– Mean baseline LVEF 55.8% (SD 13.3%).
– Median follow-up 4.2 years.
Primary and secondary events
– 223 patients experienced the primary outcome of malignant VA.
– 109 experienced the secondary outcome of advanced heart failure.
Variant-type comparisons
– Truncating variants were associated with a higher risk of malignant VA compared with missense variants: hazard ratio (HR) 1.72, 95% CI 1.19–2.48, P = .004.
– There was no significant difference between truncating and missense variants for advanced heart failure (HR 0.94, 95% CI 0.64–1.40, P = .77).
Variant location and stratified results
– For truncating variants, neither location on the LMNA gene nor transcript position (head, rod, tail) substantially changed the elevated risk of VA — truncating status conferred higher arrhythmic risk independent of position.
– In contrast, among missense variants, location mattered. On multivariable analysis, missense variants affecting the tail domain were associated with a lower risk of malignant VA (HR 0.35, 95% CI 0.16–0.78, P = .02).
– Missense variants located in exons 7–12 were similarly associated with lower VA risk (HR 0.39, 95% CI 0.17–0.89, P = .035).
Interpretation of effect sizes
– The HR of ~1.7 for truncating vs missense indicates an approximately 70% increased instantaneous risk of malignant VA in truncating variant carriers over the observed follow-up.
– The HRs of ~0.35–0.39 for tail-domain and exon 7–12 missense variants indicate those subgroups had roughly two-thirds lower hazard for malignant VA compared with other missense variants, after multivariable adjustment.
Clinical implications
– The consistent elevated arrhythmic risk in truncating variants suggests truncation status is a robust marker for arrhythmic vulnerability and may support a lower threshold for prophylactic ICD implantation in selected carriers, consistent with guideline emphasis on LMNA status as a risk modifier.
– The finding that missense variants are heterogeneous—some locations (tail domain, exons 7–12) carry substantially lower risk—suggests that fine-grained genotype information could refine risk estimates and personalize clinical decision-making, particularly in patients with preserved LVEF and no prior VA.
Expert commentary and mechanistic considerations
Biologic plausibility
– Lamin A/C form a filamentous network at the nuclear lamina and participate in nuclear structural integrity, chromatin organization, and mechano-transduction. Truncating variants commonly produce haploinsufficiency (reduced lamin A/C levels) and may destabilize the nuclear lamina broadly, leading to myocardial vulnerability to conduction system disease and VA.
– Missense variants can act through dominant-negative mechanisms or subtle functional perturbations. The observation that tail-domain missense variants and those in exons 7–12 have lower arrhythmic risk suggests certain structural regions tolerate amino-acid substitutions better or that variants there perturb functions less relevant to arrhythmogenesis.
Comparison with prior literature
– Previous series have identified LMNA variant carriers as high risk for malignant arrhythmias and suggested truncating variants may confer worse outcomes. This study extends those observations in a large international cohort and adds granularity by demonstrating that for missense variants, position along the protein and gene modulates risk.
Limitations
– Retrospective design creates potential for referral and ascertainment bias; tertiary center cohorts can over-represent severe cases.
– Variant classification relied on current pathogenic/likely pathogenic calls, but differences in functional impact among ostensibly similar variants may exist.
– Residual confounding is possible despite multivariable adjustment (e.g., family history intensity, coexisting genetic modifiers, management differences across centers).
– Outcome ascertainment varied historically (e.g., ICD programming and thresholds) and device therapy may have altered natural history.
– The study does not provide mechanistic functional data to explain why tail-domain/exon 7–12 missense variants are lower risk.
Practical considerations for clinicians
– For patients with truncating LMNA variants, clinicians should maintain a high index of suspicion for malignant VA and consider earlier or lower-threshold ICD discussion, especially when additional clinical risk markers (male sex, non-missense mutation in prior reports, non-sustained VT, reduced LVEF, conduction disease) are present.
– For carriers of missense variants, genotype-location information (tail-domain vs other domains, exon location) can inform risk communication. Importantly, ‘‘lower risk’’ is relative — close clinical follow-up, ambulatory rhythm monitoring, and reassessment of LVEF remain essential.
– Multidisciplinary care including genetic counseling is recommended; family cascade testing and surveillance strategies should incorporate genotype-informed risk but remain individualized.
Research and therapeutic implications
– Prospective registries that systematically collect genotype, functional data, and standardized phenotyping are needed to validate and calibrate risk models incorporating variant type and location.
– Functional studies (in vitro, iPSC-cardiomyocyte models, animal models) should probe why tail-domain missense variants behave differently; understanding mechanisms could reveal therapeutic targets to prevent arrhythmia or structural progression.
– Genotype-stratified clinical trials (for device therapy thresholds or precision therapeutics) could test whether variant-informed management improves outcomes.
Conclusion
This large multinational retrospective cohort demonstrates that truncating LMNA variants confer significantly higher arrhythmic risk compared with missense variants, independent of variant position, reinforcing truncation status as a key risk marker. Importantly, missense variants are heterogeneous: those affecting the tail domain and located in exons 7–12 associate with substantially lower malignant VA risk. These findings support integrating both variant type and spatial information into LMNA risk stratification and counseling while highlighting the need for prospective validation and mechanistic studies.
Funding and clinicaltrials.gov
Funding and detailed trial registration information are reported in the original publication (Bhaskaran et al., JAMA Cardiol. 2025). This analysis was retrospective and combined registry and center data; it was not a prospective interventional trial registered on ClinicalTrials.gov.
References
1. Bhaskaran A, Ben Yaou R, Helms AS, et al. Location of LMNA Variants and Clinical Outcomes in Cardiomyopathy. JAMA Cardiol. 2025 Sep 1;10(9):896-903. doi: 10.1001/jamacardio.2025.2069.
2. van Rijsingen IAW, Arbustini E, Elliott PM, et al. Risk factors for malignant ventricular arrhythmias in lamin A/C mutation carriers. Eur Heart J. 2012;33(5):??? (original article provides earlier evidence linking LMNA variants to arrhythmic risk).
(Note: consult the primary JAMA Cardiology article for detailed methods, funding, and supplementary data.)
