Original Articles
Vol. 5 No. 3 (2026): In memory of Armando D’Angelo
https://doi.org/10.4081/btvb.2026.367

Whole exome sequencing in a family with thromboangiitis obliterans

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Published: 28 August 2026
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Thromboangiitis obliterans, Buerger’s disease, whole exome sequencing

Authors

Barbara Lunghi
https://orcid.org/0000-0002-1517-4762
Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
Dario Balestra
https://orcid.org/0000-0002-6675-9429
Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
Nicole Ziliotto
https://orcid.org/0000-0003-1007-7266
Department of Biochemistry, Maastricht University, Cardiovascular Research Institute; Coagulation Profile B.V., Maastricht,, Netherlands.
Giulia Pavani
https://orcid.org/0000-0002-2522-2684
Department of Pathology and Laboratory Medicine, Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, PA, United States.
Matteo Bovolenta
https://orcid.org/0000-0002-9937-009X
Department of Translational Medicine, University of Ferrara, Italy.
Patrizia Della Valle
https://orcid.org/0000-0002-2790-3088
Unit of Coagulation Service and Thrombosis Research, IRCCS San Raffaele Hospital, Milan, Italy.
Mirko Pinotti
https://orcid.org/0000-0002-4114-7055
Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
Giovanna Marchetti
https://orcid.org/0000-0002-5510-6393
Department of Neuroscience and Rehabilitation, University of Ferrara, Italy.
Armando D'Angelo
https://orcid.org/0000-0002-9857-4509
Unit of Coagulation Service and Thrombosis Research, IRCCS San Raffaele Hospital, Milan, Italy.
Francesco Bernardi
francesco.bernardi@unife.it
https://orcid.org/0000-0003-0305-2212
Department of Life Science and Biotechnology , University of Ferrara, Italy.

Low-frequency candidates for susceptibility to thromboangiitis obliterans (TAO) were investigated by whole exome sequencing in a family with a young member with migrating thrombophlebitis, artery thrombosis, and ulcerations followed by below-knee amputation. Filtering among 193 candidates for venous thromboembolism (VTE) detected rare heterozygous variants: the PPIF (peptidylprolyl-isomerase F) frameshift p.Tyr121fs*0 [minor allele frequency (MAF)= 0.000004], the F2 (thrombin) synonymous/splicing p.Gly271=, and 5 missense variants. Among these, the novel PTGIR (prostaglandin I2 receptor) p.Tyr144Asn would interfere with transmembrane helix interaction, and potentially decrease prostacyclin response. Filtering among 92 genes, suggested by previous genomic and transcriptomic studies in TAO patients, detected a rare combination of HLA-DQB1 alleles, and two in linkage variants (MAF=0.0003) in titin (TTN). Interestingly, TTN is also reported among VTE proteome alterations. By exploring the whole exome, the novel BET1 nonsense p.Glu33Ter change may indirectly influence hemostasis and endothelial integrity. This study pinpoints novel TAO candidate genetic components for further investigation

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Ethics Approval

The study, an investigator-initiated institutional review board-approved investigation for improved genetic diagnosis, was conducted according to the guidelines of the Declaration of Helsinki, and approved (June 2015) by the Institutional Review Board of the San Raffaele Hospital.

CRediT authorship contribution

GM, ADA and FB study concept; PDV and ADA collected clinical data; PDV performed laboratory analysis; BL, NZ, GP and MB, methodology; NZ, GP and MB bioinformatics analysis; BL, NZ and DB data analysis; BL, GM and FB data interpretation and resources; BL, MP, GM and FB writing-review and editing; BL and DB preparation of tables and figure; FB supervision. All the authors approved the final manuscript. 

Supporting Agencies

This research was funded by FAR (Fondo di Ateneo per la Ricerca Scientifica) of the University of Ferrara

Data Availability Statement

All relevant data are included in the manuscript. Additional original data will be made available by contacting the corresponding author within the regulations of ethical approval. 

How to Cite



1.
Lunghi B, Balestra D, Ziliotto N, Pavani G, Bovolenta M, Della Valle P, et al. Whole exome sequencing in a family with thromboangiitis obliterans. Bleeding Thromb Vasc Biol [Internet]. 2026 Aug. 28 [cited 2026 Oct. 15];5(3). Available from: https://www.btvb.org/btvb/article/view/367
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