LMNA – Atrioventricular Block

Lamin A/C (LMNA) variants are established causes of autosomal dominant atrioventricular block (AVB; MONDO:0000465), often accompanied by conduction system disease and late-onset dilated cardiomyopathy. Initial linkage in a Chinese family identified a heterozygous c.244G>A (p.Glu82Lys) variant co-segregating with AVB in six individuals, absent in 200 controls (6 probands) (PMID:20155465).

In a series of 73 dilated cardiomyopathy (DCM) cases with AVB, 5/15 familial autosomal dominant DCM-AVB probands carried LMNA mutations (including c.289A>G (p.Lys97Glu), c.568C>T (p.Arg190Trp), c.949G>A (p.Glu317Lys), c.951G>T (p.Glu317Asp), and an insertion) demonstrating robust segregation and reduced LMNA nuclear expression (PMID:11897440).

Population screening in 226 young AVB patients revealed pathogenic or likely pathogenic LMNA variants in 5 individuals (5%), all with family histories of AVB or sudden cardiac death, underscoring the gene’s contribution to early-onset conduction disease (PMID:35470684). In an independent cohort of 41 patients T (p.Tyr481Ter), c.936+1G>T, c.646C>T (p.Arg216Cys)), associated with arrhythmias and atrial/ventricular enlargement (PMID:38048861).

The LMNA variant spectrum in AVB spans missense (p.Glu82Lys), nonsense (p.Tyr481Ter), frameshift (c.383dup (p.Ala129fs)), splice-site (c.936+1G>T) and multi-exon deletions, all following autosomal dominant inheritance. Several variants, such as p.Glu82Lys, recur in Chinese cohorts, suggesting possible founder effects in specific populations.

Experimental models support a dominant-negative mechanism: mice homozygous for Lmna p.Asn195Lys exhibit early lethal arrhythmias, conduction block, mislocalization of connexins 40/43 and disrupted intercalated disks, recapitulating human AVB (PMID:15972724). In vitro, p.Glu82Lys lamin A mislocalizes from the nuclear envelope, disrupts emerin distribution and induces nuclear membrane and heterochromatin abnormalities also seen in patient cardiomyocytes (PMID:16630578).

No conflicting evidence has emerged; all reports consistently link LMNA dysfunction to AV conduction defects. The strength of genetic segregation across multiple families, replication in large cohorts, and concordant functional data justify a Definitive association.

Key Take-home: LMNA genetic testing should be incorporated into the diagnostic workup of young or familial AVB to guide early intervention and familial risk assessment.

References

• Journal of Huazhong University of Science and Technology. Medical Sciences • 2010 • Identification of a new lamin A/C mutation in a Chinese family affected with atrioventricular block as the prominent phenotype. PMID:20155465
• Journal of the American College of Cardiology • 2002 • Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. PMID:11897440
• Journal of the American Heart Association • 2022 • Diagnostic Yield of Genetic Testing in Young Patients With Atrioventricular Block of Unknown Cause. PMID:35470684
• 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
• Biochemical and Biophysical Research Communications • 2006 • Mutation Glu82Lys in lamin A/C gene is associated with cardiomyopathy and conduction defect. PMID:16630578

Evidence Based Scoring (AI generated)