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

Nicole Revencu; Astrid Eijkelenboom; Claire Bracquemart; Pia Alhopuro; Judith Armstrong; Eulalia Baselga; Claudia Cesario; Maria Lisa Dentici; Melanie Eyries; Sofia Frisk; Helena Gásdal Karstensen; Nagore Gene-Olaciregui; Sirpa Kivirikko; Cinzia Lavarino; Inger-Lise Mero; Rodolphe Michiels; Elisa Pisaneschi; Bitten Schönewolf-Greulich; Ilse Wieland; Martin Zenker; Miikka Vikkula

doi:10.1186/s13023-024-03196-9

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

Orphanet J Rare Dis. 2024 May 22;19(1):213. doi: 10.1186/s13023-024-03196-9.

Authors

Nicole Revencu^#¹, Astrid Eijkelenboom^#², Claire Bracquemart^#³, Pia Alhopuro⁴, Judith Armstrong⁵, Eulalia Baselga⁶, Claudia Cesario⁷, Maria Lisa Dentici⁸, Melanie Eyries⁹, Sofia Frisk¹⁰, Helena Gásdal Karstensen¹¹, Nagore Gene-Olaciregui¹², Sirpa Kivirikko¹³, Cinzia Lavarino¹², Inger-Lise Mero¹⁴, Rodolphe Michiels¹, Elisa Pisaneschi⁷, Bitten Schönewolf-Greulich¹¹, Ilse Wieland¹⁵, Martin Zenker^#¹⁵, Miikka Vikkula^#^{16

17

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Affiliations

¹ Center for Human Genetics, Cliniques universitaires Saint-Luc, University of Louvain, VASCERN VASCA European Reference Centre, Brussels, Belgium.
² Department of Pathology, Radboud University Medical Center, VASCERN VASCA European Reference Centre, PO Box 9101, 6500, HB, Nijmegen, the Netherlands.
³ Normandie Univ, UNICAEN, Service de Génétique, CHU Caen Normandie, BIOTARGEN EA 7450, VASCERN VASCA European Reference Centre, Caen, 14000, France.
⁴ HUS Diagnostic Center, Laboratory of Genetics, University of Helsinki and Helsinki University Hospital, VASCERN VASCA European Reference Centre, Helsinki, Finland.
⁵ Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, and Genomic Unit, Molecular and Genetic Medicine Section, Hospital Sant Joan de Déu, VASCERN VASCA European Reference Centre, Barcelona, Spain.
⁶ Department of Dermatology, Hospital Sant Joan de Deu, VASCERN VASCA European Reference Centre, Barcelona, Spain.
⁷ Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital and Research Institute, IRCCS, VASCERN VASCA European Reference Centre, Rome, Italy.
⁸ Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, VASCERN VASCA European Reference Centre, 00165, Rome, Italy.
⁹ Sorbonne Université, Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, VASCERN VASCA European Reference Centre, Paris, France.
¹⁰ Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Clinical Genetics, Karolinska University Hospital, VASCERN VASCA European Reference Centre, Stockholm, Sweden.
¹¹ Department of Genetics, Center of Diagnostics, Copenhagen University Hospital - Rigshospitalet, VASCERN VASCA European Reference Centre, Copenhagen, Denmark.
¹² Laboratory of Molecular Oncology, Pediatric Cancer Center Barcelona, Hospital Sant Joan de Déu, VASCERN VASCA European Reference Centre, Barcelona, Spain.
¹³ Department of Clinical Genetics, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, VASCERN VASCA European Reference Centre, Helsinki, Finland.
¹⁴ Department of Medical Genetics, Oslo University Hospital, VASCERN VASCA European Reference Centre, Oslo, Norway.
¹⁵ Institute of Human Genetics, University Hospital Otto-Von-Guericke-University, Magdeburg, Germany.
¹⁶ Center for Vascular Anomalies, Cliniques Universitaires Saint-Luc, Brussels, Belgium. miikka.vikkula@uclouvain.be.
¹⁷ Human Molecular Genetics , de Duve Institute, University of Louvain, VASCERN VASCA European Reference Centre, Brussels, Belgium. miikka.vikkula@uclouvain.be.
¹⁸ WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, 1300, Wavre, Belgium. miikka.vikkula@uclouvain.be.

^# Contributed equally.

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/ ).

Keywords: ERN; Gene curation; ISSVA; Mosaic; Postzygotic; Precision medicine; Somatic; VASCERN-VASCA; Vascular malformation.

MeSH terms

Genetic Association Studies
Genetic Testing* / methods
Humans
Vascular Malformations* / diagnosis
Vascular Malformations* / genetics
Vascular Malformations* / pathology

Abstract

MeSH terms

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