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

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Epidemiology

Background:

• Cardiac laminopathies, caused by LMNA gene mutations, present significant risks including conduction disorders, arrhythmias, and heart failure.
• The LMNA c.1609-3C>G variant is the most prevalent mutation in Quebec, necessitating detailed characterization.
• Understanding this specific variant is crucial for managing cardiac risks in affected populations.

Purpose of the Study:

• To clinically and functionally characterize the prevalent LMNA c.1609-3C>G variant.
• To evaluate the accuracy of existing risk prediction models for this specific mutation.
• To elucidate the unique cardiac phenotype associated with LMNA c.1609-3C>G.

Main Methods:

• A single-center cohort study design was employed.
• Clinical data were correlated with genome-wide genotyping.
• Functional in vitro experiments were conducted to understand the variant's impact.

Main Results:

• The study analyzed 77 heterozygous carriers from 15 French-Canadian families.
• Nearly all patients (98%) developed advanced atrio-ventricular conduction disorders.
• A sequential cardiac manifestation was observed: conduction disorders preceded cardiomyopathy/arrhythmias by 10-15 years.

Conclusions:

• LMNA c.1609-3C>G is a French-Canadian founder variant with a distinct, age-dependent cardiac phenotype.
• Advanced atrio-ventricular conduction disease progresses rapidly, preceding other cardiac issues.
• Current risk prediction models are inadequate for stratifying patients with the LMNA c.1609-3C>G variant.