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Background <p>Desmoglein-2 (<i>DSG2</i>) is an essential cardiac desmosomal cadherin, and its alteration underlies a broad spectrum of arrhythmogenic cardiomyopathy (ACM). Yet, the clinical significance of many <i>DSG2</i> variants remains uncertain. This study aimed to systematically characterize the spectrum, structural impact, and clinical relevance of <i>DSG2</i> variants by integrating large-scale genomic evidence, published data, and a deeply phenotyped validation cohort.</p> Methods <p>We conducted a systematic literature review (115 studies; 145 curated variants) and analyzed population-scale datasets (3570 variants in gnomAD; 1847 in ClinVar). All variants were uniformly reclassified following ACMG/ClinGen criteria. A validation cohort of 95 Italian <i>DSG2</i>-carriers underwent detailed phenotyping. Structural modeling via AlphaFold, supported protein modeling, calcium-binding site prediction, and DynaMut stability analysis were performed to evaluate the functional consequences of key variants.</p> Results <p>Literature and database integration reveal domain-specific variant clustering, with high-impact missense variants enriched in calcium-binding extracellular domains, the furin cleavage site, and the intracellular PKP2-binding region. In the validation cohort, penetrance among genotype-positive relatives is 42%, while 13% of definite ACM cases experience major ventricular arrhythmias; transplantation and mortality each occur in 3%. Biallelic and digenic variants are associated with earlier onset and more severe biventricular involvement. Structural modeling confirms that pathogenic missense substitutions destabilize DSG2 architecture or impair calcium-dependent adhesion.</p> Conclusions <p>This study refines the classification of <i>DSG2</i> variants and highlights the importance of domain-level and multilocus interpretation in ACM. These findings support comprehensive genetic screening, structural modeling for variant assessment, and lifelong follow-up of <i>DSG2</i> carriers to improve diagnosis and risk stratification.</p>

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Integrative genomic and literature assessment of desmoglein 2-related arrhythmogenic cardiomyopathy with Italian cohort validation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Serena Pinci,
  • Rudy Celeghin,
  • Marika Martini,
  • Monica De Gaspari,
  • Maria Bueno Marinas,
  • Giulia Tosato,
  • Francesca Dalla Zanna,
  • Marco Cason,
  • Ilaria Rigato,
  • Gaetano Thiene,
  • Stefania Rizzo,
  • Domenico Corrado,
  • Cristina Basso,
  • Barbara Bauce,
  • Kalliopi Pilichou

摘要

Background

Desmoglein-2 (DSG2) is an essential cardiac desmosomal cadherin, and its alteration underlies a broad spectrum of arrhythmogenic cardiomyopathy (ACM). Yet, the clinical significance of many DSG2 variants remains uncertain. This study aimed to systematically characterize the spectrum, structural impact, and clinical relevance of DSG2 variants by integrating large-scale genomic evidence, published data, and a deeply phenotyped validation cohort.

Methods

We conducted a systematic literature review (115 studies; 145 curated variants) and analyzed population-scale datasets (3570 variants in gnomAD; 1847 in ClinVar). All variants were uniformly reclassified following ACMG/ClinGen criteria. A validation cohort of 95 Italian DSG2-carriers underwent detailed phenotyping. Structural modeling via AlphaFold, supported protein modeling, calcium-binding site prediction, and DynaMut stability analysis were performed to evaluate the functional consequences of key variants.

Results

Literature and database integration reveal domain-specific variant clustering, with high-impact missense variants enriched in calcium-binding extracellular domains, the furin cleavage site, and the intracellular PKP2-binding region. In the validation cohort, penetrance among genotype-positive relatives is 42%, while 13% of definite ACM cases experience major ventricular arrhythmias; transplantation and mortality each occur in 3%. Biallelic and digenic variants are associated with earlier onset and more severe biventricular involvement. Structural modeling confirms that pathogenic missense substitutions destabilize DSG2 architecture or impair calcium-dependent adhesion.

Conclusions

This study refines the classification of DSG2 variants and highlights the importance of domain-level and multilocus interpretation in ACM. These findings support comprehensive genetic screening, structural modeling for variant assessment, and lifelong follow-up of DSG2 carriers to improve diagnosis and risk stratification.