LMNA – Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant cardiomyopathy characterized by fibrofatty replacement of the myocardium, ventricular arrhythmias, and sudden cardiac death. While most cases are due to desmosomal gene mutations, pathogenic variants in the LMNA gene have been increasingly reported in ARVC patients, particularly those with conduction defects and family history of sudden death. Recognition of LMNA‐mediated ARVC expands the diagnostic spectrum beyond classical desmosomal causes and informs precision risk stratification and management.

Heterozygous LMNA variants have been identified in at least 7 independent ARVC probands, including a large four-generation Italian kindred with a novel exon 2 duplication (c.418_438dup) segregating with disease in 5 affected relatives ([PMID:25837155]). Additional unrelated cases include three LMNA mutation–positive patients without desmosomal variants in a cohort of 108 ARVC families ([PMID:22199124]) and two Japanese probands identified among 57 ARVC patients ([PMID:26620845]). The recurrent detection of distinct LMNA missense and frameshift mutations in unrelated families, all absent in ethnically matched controls, supports a pathogenic role under an autosomal dominant inheritance model.

Segregation analysis of the c.418_438dup variant demonstrated complete co-segregation in 5 affected relatives across four generations, with absence in 250 healthy controls ([PMID:25837155]). Although some large ARVC cohorts screened (n=65) failed to identify LMNA‐causal variants ([PMID:27896052]), the overall segregation evidence in multiplex families provides moderate support for pathogenicity in selected clinical contexts.

Functional studies further corroborate a haploinsufficiency/structural mechanism: cardiomyocytes transfected with mutant LMNA constructs exhibit increased nuclear envelope fragility and stress-induced apoptosis consistent with ARVC pathology ([PMID:25837155]). Moreover, a knock-in mouse expressing the LMNA-N195K variant recapitulates human conduction defects and arrhythmia, leading to premature death ([PMID:15972724]). These concordant in vitro and in vivo data align with the human phenotype and underscore a non-desmosomal pathogenic pathway.

Conflicting evidence arises from limited-size screening studies that did not detect LMNA mutations in some ARVC cohorts ([PMID:27896052]), suggesting that LMNA contributes to a minority of ARVC cases and highlighting locus heterogeneity. Nonetheless, when present, LMNA variants necessitate tailored surveillance for conduction disease and systemic laminopathy manifestations.

Integration of genetic and experimental findings supports a Moderate clinical validity classification for the LMNA–ARVC association. Heterozygous LMNA mutations should be considered in ARVC patients, particularly those with ECG conduction abnormalities or extracardiac laminopathy features. Key take-home: LMNA mutation testing adds diagnostic and prognostic value in ARVC, guiding clinical management and familial risk assessment.

References

• PLoS One • 2015 • Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy. PMID:25837155
• European Heart Journal • 2012 • Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy. PMID:22199124
• Journal of Cardiology • 2016 • LMNA cardiomyopathy detected in Japanese arrhythmogenic right ventricular cardiomyopathy cohort. PMID:26620845
• Human Molecular Genetics • 2005 • Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice. PMID:15972724
• Applied & Translational Genomics • 2012 • Mutation analysis of the candidate genes SCN1B-4B, FHL1, and LMNA in patients with arrhythmogenic right ventricular cardiomyopathy. PMID:27896052

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