Homozygous Desmocollin-2 Mutations and Arrhythmogenic Cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Diseases

Background:

• Dominant mutations in the desmocollin-2 (DSC2) gene are a known cause of arrhythmogenic cardiomyopathy (ACM).
• Recessive DSC2 mutations are infrequently observed and typically linked to cardiac or cardiocutaneous phenotypes.
• The clinical impact of homozygous DSC2 mutations in ACM remains largely uncharacterized.

Purpose of the Study:

• To investigate the clinical consequences of a homozygous founder mutation in the DSC2 gene on arrhythmogenic cardiomyopathy (ACM) presentation.
• To determine the prevalence and phenotype associated with recessive DSC2 mutations in Italian ACM patients.

Main Methods:

• Exon-by-exon sequencing of the DSC2 gene in 94 ACM index patients.
• Genetic and clinical evaluation of affected families to assess segregation of the mutation and phenotype.
• Haplotype analysis to confirm common ancestry for mutation carriers.

Main Results:

• A homozygous founder mutation, c.536A>G (p.D179G), was identified in 4 out of 5 ACM patients carrying DSC2 mutations.
• Homozygous carriers presented with severe biventricular cardiomyopathy, distinct from hair or skin abnormalities.
• Heterozygous carriers were largely asymptomatic, with one mild case presenting additional genetic variants.

Conclusions:

• This study identifies the first homozygous founder mutation in DSC2 among Italian ACM probands.
• Recessive DSC2 mutations are associated with predominantly biventricular forms of arrhythmogenic cardiomyopathy.
• These findings underscore the importance of investigating recessive genetic causes in ACM.