Abstract
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.
Plain language summary
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease that can cause abnormal rhythms and sudden cardiac death, often in young adults. This study focused on the DSG2 gene, which helps heart cells stick together. We combined genetic data from large population databases, published studies, and a group of Italian patients with ACM to understand how different DSG2 changes affect disease risk. We found that disease severity depends not only on the type of genetic change but also on the location within the gene and whether other related genes are involved. These findings improve understanding of inherited heart disease and support more accurate genetic testing and follow-up for affected families.
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Data availability
The full-length DSG2 protein structure was obtained from the AlphaFold Protein Structure Database (UniProt accession: Q14126; model AF-Q14126-F1, version v4). DSG2 genetic variants were systematically collected from publicly available databases, including gnomAD v4.1.0 (https://gnomad.broadinstitute.org) and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). No newly generated sequencing data were deposited in public repositories. Clinical data, including ECG, echocardiography, and CMR evaluations, were collected according to the current ESC 2023 Guidelines. Due to ethical and privacy constraints related to human genetic and clinical data, the raw data generated and analyzed in this study are not publicly available. Access to the raw data may be granted upon reasonable request and subject to approval by the corresponding author, in accordance with institutional policies and applicable regulations. Requests should be addressed to Kalliopi Pilichou (email: kalliopi.pilichou@unipd.it). A response to data access requests will be provided within 15 working days of receipt. Approved access will be subject to a data use agreement defining conditions of use, including restrictions on data sharing, requirements for appropriate data protection, and limitation of use to non-commercial research purposes.
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Acknowledgements
This work was supported by the Italian Ministry of University and Research (MUR) (PRIN grant 20229FE439—CUP C53D23004670006 “The mechanistic link between genetic substrate and immune reactions in inflammatory cardiomyopathies”), Rome; the Registry for Cardio-cerebro-vascular Pathology, Veneto region, Venice; and ARCA (Associazione Ricerche Cardiopatie Aritmiche), Padova, Italy. RC and MBM are Postdoc Fellows supported by the Italian Ministry of Health, PNRR Next-Generation EU grant PNRR-MR1-2022-12376614—CUP I93C22000570006 “Machine learning approach for inherited Arrhythmic cardiomyopathies re-classification and risk stratification: from imaging to genomics. “ Funded by the European Union—Next Generation EU—NRRP M6C2—Investment 2.1 “Enhancement and strengthening of biomedical research in the NHS.
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Conceptualization: K.P. Formal analysis: S.P., M.C., M.B.M., and R.C. Funding acquisition: K.P., C.B., D.C., and G.Th. Investigation: S.P. Methodology: S.P., M.C., M.B.M., R.C., F.D.Z., G.T., and M.D.G. Clinical investigation: M.M., I.R., S.R., M.D.G., B.B., and C.B. Resources: K.P. and C.B. Software: S.P., M.C., M.B.M., and R.C. Supervision: K.P. Writing original draft: S.P. and K.P. Writing—review and editing: B.B., G.Th., C.B., and K.P. All authors have read and agreed to the published version of the manuscript.
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Communications Medicine thanks Roddy Walsh, Jasper J. van der Smagt, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Pinci, S., Celeghin, R., Martini, M. et al. Integrative genomic and literature assessment of desmoglein 2-related arrhythmogenic cardiomyopathy with Italian cohort validation. Commun Med (2026). https://doi.org/10.1038/s43856-026-01416-w
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DOI: https://doi.org/10.1038/s43856-026-01416-w
