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PreprintCited by 1Cardiovascular Effects of ExerciseCardiac electrophysiology and arrhythmiasCardiomyopathy and Myosin Studies

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Desmoglein-2 related Arrhythmogenic Cardiomyopathy: Integrative Genomic and Literature-based analysis with an Italian cohort-Level Validation

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Pilichou, Kalliopi, Pinci, Serena, Celeghin, Rudy, Martini, Marika, De Gaspari, Monica, Marinas, Maria Bueno, Tosato, Giulia, Zanna, Francesca Dalla, Cason, Marco, Rigato, Ilaria, Thiene, Gaetano, Rizzo, Stefania, Corrado, Domenico, Basso, Cristina, Bauce, Barbara·2025·Communications Medicine
DOI 10.21203/rs.3.rs-6957155/v1PMC PMC12987970

Preprint — published as 10.1038/s43856-026-01416-w

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Abstract

Desmoglein-2 (DSG2) is a crucial desmosomal cadherin expressed in cardiomyocytes that contributes significantly to the development of arrhythmogenic cardiomyopathy (ACM), a condition characterized by variable onset and clinical presentation. In this study, we conducted an integrative analysis that merges a systematic review of the literature, data from large-scale population databases, and findings from a well-phenotyped Italian ACM validation cohort (n = 95). While pathogenic variants, “hot-VUS,” and copy number alterations were primarily located in calcium-binding extracellular domains, the furin cleavage site, and cytoplasmic anchoring motifs, these alone were insufficient to explain disease manifestation, with penetrance estimated at just 42%. In contrast, biallelic and digenic variants correlated with earlier onset, more severe biventricular involvement, and complete penetrance. Structural modeling and protein stability analyses confirmed disruption of key functional domains. These results underscore the complexity of DSG2-related ACM and advocate for domain- and multilocus-informed diagnostic strategies, along with comprehensive genetic screening and sustained clinical follow-up for effective risk stratification in affected families.

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Metadata

Authors
Pilichou, K., Pinci, S., Celeghin, R., Martini, M., De Gaspari, M., Marinas, M. B., Tosato, G., Zanna, F. D., Cason, M., Rigato, I., Thiene, G., Rizzo, S., Corrado, D., Basso, C., & Bauce, B.
Affiliations
  • University of Padua (IT)
  • University of Padua
  • Azienda Ospedale - Università Padova (IT)
Corresponding author
Pilichou, Kalliopi
ORCID
Venue
Communications Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-08-27
Volume
6
Issue
1
ISSN
2730-664X (ISSN-L)
DOI
10.21203/rs.3.rs-6957155/v1
PMC
PMC12987970
OpenAlex
W7128161746
Cited by
1
References
1
Citations by year
2026: 1
FWCI
4.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Medicine (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • European Commission (NRRP M6C2)
  • Ministero della Salute (NRRP M6C2)
  • Regione del Veneto
  • NextGenerationEU
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
desmoglein 2, arrhythmogenic cardiomyopathy, desmosomal cadherins, genetic variants, variant interpretation, penetrance, genotype-phenotype correlation, calcium-binding domain, furin cleavage site, protein stability, structural modeling, biallelic variants, ventricular arrhythmias, sudden cardiac death, genetic screening

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