Next-generation sequencing identified novel Desmoplakin frame-shift variant in patients with Arrhythmogenic...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic basis of cardiomyopathies

Background:

• Arrhythmogenic cardiomyopathy (AC) is a primary cause of sudden cardiac death (SCD).
• Mutations in cardiac desmosomes are implicated in AC pathogenesis.
• The genetic underpinnings of AC in individual families often remain unclear.

Purpose of the Study:

• To investigate the genetic cause of AC in a 4-generation family with a history of syncope, ventricular arrhythmias, and SCD.
• To characterize the functional consequences of a newly identified genetic variant in Desmoplakin (DSP).

Main Methods:

• Recruited a 4-generation family with a history of syncope, ventricular arrhythmias, and SCD.
• Performed targeted next-generation sequencing (NGS) and Sanger sequencing to identify genetic variants.
• Constructed plasmids with wild-type (WT) and mutant DSP for functional studies.
• Utilized real-time PCR, western blot, and immunofluorescence to assess protein expression and localization.

Main Results:

• Identified a novel heterozygous frame-shift variant (c.832delG) in the DSP gene in 5 family members.
• The DSP variant resulted in a truncated protein, confirmed by molecular analyses.
• Cardiac MRI revealed significant cardiac abnormalities, including right ventricular dysfunction and fatty infiltration, consistent with AC.
• In vitro studies showed altered DSP expression and downstream signaling pathway changes (Wnt/β-catenin).

Conclusions:

• The novel c.832delG variant in DSP is strongly associated with arrhythmogenic cardiomyopathy in this family.
• The mutation likely disrupts cardiac function through alterations in desmosome integrity and potentially the Wnt/β-catenin signaling pathway.