MINI REVIEW article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1605727
This article is part of the Research TopicGenetic and Immunological Insights into Angioedema Without WhealsView all 9 articles
Incidental findings related to genes associated to HAE-nC1INH: How to proceed?
Provisionally accepted
- 1Department of Immunology & Histocompatibility, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
- 24th Department of Internal Medicine, Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece
- 3Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
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In contrast to hereditary angioedema (HAE) due to C1-inhibitor deficiency, the detection of pathogenic variants in genes linked to HAE with normal C1 inhibitor levels (HAE-nC1INH) is required for the diagnosis of the corresponding types of the disease. The mainstreaming of genomic technology and the increasing use of next generation sequencing have increased the possibility of an unintentional detection of HAE-nC1INH pathogenic variants and allowed the incidental finding of variants of uncertain significance (VUS) in the relevant genes. Apart from F12 and PLG pathogenic variants, the current level of evidence on the prevalence and penetrance of variants associated with HAE-nC1INH does not support the reporting of their incidental finding. On the other hand, although VUS should not be used in clinical decision-making, further consideration is warranted (a) for VUS found in exon 9 of the F12 gene after a diagnostic genetic analysis of individuals either with or without personal or family history of angioedema, and (b) for VUS found in any of the other genes linked to HAE-nC1INH, after genetic analysis performed in the context of differential diagnosis of angioedema cases. Given the complexity of interpreting, reporting and communicating incidental findings, a close partnership between patients, clinicians, laboratory geneticists and genetic counsellors is essential to optimize the management of these results.
Keywords: hereditary angioedema, Incidental Findings, incidental VUS, Penetrance, secondary findings, variants of uncertain significance
Received: 03 Apr 2025; Accepted: 29 May 2025.
Copyright: © 2025 Germenis and Sanoudou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Anastasios E Germenis, Department of Immunology & Histocompatibility, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, 41500, Greece
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