Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA

Nicole Revencu (1, 2) , Astrid Eijkelenboom (3) , Claire Bracquemart (4, 5) , Pia Alhopuro , Judith Armstrong (6, 7) , Eulalia Baselga , Claudia Cesario , Maria Lisa Dentici (8) , Melanie Eyries (9) , Sofia Frisk , Helena Gásdal Karstensen , Nagore Gene-Olaciregui , Sirpa Kivirikko , Cinzia Lavarino , Inger-Lise Mero (10) , Rodolphe Michiels , Elisa Pisaneschi , Bitten Schönewolf-Greulich , Ilse Wieland (11) , Martin Zenker (11) , Miikka Vikkula (12)

1 Cliniques Universitaires Saint-Luc [Bruxelles]
2 Centre de Génétique Humaine
3 Department of Molecular Cancer Research
4 Service de Génétique [CHU Caen]
5 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires
6 Hospital Sant Joan de Déu
7 CIBERER - Centro de Investigación Biomédica en Red de Enfermedades Raras
8 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
9 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
10 Oslo University Hospital [Oslo]
11 OVGU - Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg]
12 WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, 1300, Wavre

Abstract Background Vascular anomalies caused by somatic (postzygotic) variants are clinically and genetically heterogeneous diseases with overlapping or distinct entities. The genetic knowledge in this field is rapidly growing, and genetic testing is now part of the diagnostic workup alongside the clinical, radiological and histopathological data. Nonetheless, access to genetic testing is still limited, and there is significant heterogeneity across the approaches used by the diagnostic laboratories, with direct consequences on test sensitivity and accuracy. The clinical utility of genetic testing is expected to increase progressively with improved theragnostics, which will be based on information about the efficacy and safety of the emerging drugs and future molecules. The aim of this study was to make recommendations for optimising and guiding the diagnostic genetic testing for somatic variants in patients with vascular malformations. Results Physicians and lab specialists from 11 multidisciplinary European centres for vascular anomalies reviewed the genes identified to date as being involved in non-hereditary vascular malformations, evaluated gene–disease associations, and made recommendations about the technical aspects for identification of low-level mosaicism and variant interpretation. A core list of 24 genes were selected based on the current practices in the participating laboratories, the ISSVA classification and the literature. In total 45 gene–phenotype associations were evaluated: 16 were considered definitive, 16 strong, 3 moderate, 7 limited and 3 with no evidence. Conclusions This work provides a detailed evidence-based view of the gene–disease associations in the field of vascular malformations caused by somatic variants. Knowing both the gene–phenotype relationships and the strength of the associations greatly help laboratories in data interpretation and eventually in the clinical diagnosis. This study reflects the state of knowledge as of mid-2023 and will be regularly updated on the VASCERN-VASCA website (VASCERN-VASCA, https://vascern.eu/groupe/vascular-anomalies/ ).

Domaines: Génétique humaine

Nicole Revencu, Astrid Eijkelenboom, Claire Bracquemart, Pia Alhopuro, Judith Armstrong, et al.. Assessment of gene–disease associations and recommendations for genetic testing for somatic variants in vascular anomalies by VASCERN-VASCA. Orphanet Journal of Rare Diseases, 2024, 19 (1), pp.213. ⟨10.1186/s13023-024-03196-9⟩. ⟨hal-04586607⟩