LMNA c.1609-3C>G is a French-Canadian Founder Variant With Age-Dependent Sequential Cardiac Abnormalities

Cardiac laminopathies are characterized by a high risk of progressive atrio-ventricular conduction disorders, ventricular arrhythmia and advanced heart failure. The aim of this study was the clinical and functional characterization of the LMNA c.1609-3C>G variant, which is the most prevalent LMNA mutation in the Province of Quebec and to test the accuracy of current risk prediction models for this particular variant.

Single-center cohort study. Correlation of clinical data with genome-wide genotyping and functional in vitro experiments.

The study cohort included a total of 77 heterozygous carriers (61% females) of the LMNA c.1609-3C>G variant from 15 apparently unrelated French-Canadian families. Overall, 98% of affected patients developed advanced atrio-ventricular conduction disorders, 44% disease-related cardiomyopathy and 11.5% ventricular arrhythmias. Severe cardiac phenotypes were observed in 14/61 (23%) affected individuals. LMNA c.1609-3C>G is associated with a sequential, age-dependent, manifestation of cardiac abnormalities: AV conduction disorders preceding the manifestation of cardiomyopathy and/or ventricular arrhythmias by 10-15 years. The mean age of ventricular arrhythmias was 64.5±7.1 years. Haplotype analysis showed that LMNA c.1609-3C>G is a French-Canadian founder variant with an estimated age of 259 years. The current, guidelines-endorsed risk prediction model performed poorly for the LMNA c.1609-3C>G variant.

LMNA c.1609-3C>G is a French-Canadian founder variant with a unique phenotype of sequential, age-dependent cardiac abnormalities The rate of rapidly progressive advanced AV conduction disease is extremely high preceding the development of cardiomyopathy and ventricular arrhythmia by 10-15 years. Current risk prediction models do not accurately stratify patients with LMNA c.1609-3C>G.