Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP)...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Epidemiology

Background:

• Truncating variants in desmoplakin (DSPtv) are a significant cause of arrhythmogenic cardiomyopathy.
• The precise genetic architecture and genotype-specific risk factors for DSPtv cardiomyopathy remain incompletely understood.
• This study aimed to evaluate the phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy.

Approach:

• A multi-center international study included probands with DSPtv and cardiac phenotypes, along with gene-positive family members.
• Clinical data, family history, and event-free survival from ventricular arrhythmia were assessed.
• Variant location was compared between cases and controls, with a literature review of reported DSPtv.

Key Points:

• The study analyzed 98 probands and 72 family members, with 146 clinically affected individuals diagnosed with DSPtv.
• Ventricular arrhythmias occurred in 33% of individuals, with DSPtv location and proband status identified as independent risk factors.
• Variants in cases were significantly more likely to occur in regions leading to nonsense-mediated decay of major DSP isoforms compared to controls (83.6% vs 16.4%).

Conclusions:

• Variant location is a novel risk factor for ventricular arrhythmia in DSPtv cardiomyopathy.
• This finding can inform variant interpretation and improve the precision of clinical management for affected individuals.
• The study provides critical insights into the genetic basis and clinical manifestations of DSPtv cardiomyopathy.