Genotype-Specific Outcomes of Desmosomal Cardiomyopathies.

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Desmosomal gene variants (DGVs) are linked to arrhythmogenic cardiomyopathy (ACM).
• Limited data exists on genotype-specific outcomes in ACM patients with DGVs.
• This study addresses the need for genotype-specific risk stratification in DGV carriers.

Purpose of the Study:

• To investigate genotype-specific risks for life-threatening arrhythmic events and heart failure (HF) in desmosomal gene variant carriers.
• To identify specific desmosomal gene variants associated with distinct clinical outcomes in ACM.
• To understand how variant type and location influence ACM progression.

Main Methods:

• A cohort study including 533 patients with pathogenic or rare variants of uncertain significance in desmosomal genes.
• Defined arrhythmic endpoint as sudden cardiac death, aborted cardiac arrest, or hemodynamically unstable ventricular tachycardia.
• Defined end-stage heart failure (HF) outcome as fatal HF episode or cardiac transplantation.

Main Results:

• Non-missense DSP variants, hotspot missense variants in DSP and PKP2, male sex, and double DGVs were associated with increased risk of life-threatening arrhythmic events.
• Non-missense DSP variants and double DGVs were associated with an increased risk of end-stage HF.
• PKP2 variants were the most common single DGV (40%), followed by DSP (30%) and DSG2 (18%).

Conclusions:

• Genotype significantly influences arrhythmic and HF outcomes in DGV carriers.
• The type and location of desmosomal gene variants modulate the clinical course of arrhythmogenic cardiomyopathy.
• Findings support genotype-guided management strategies for ACM patients.