Clinical utility of panel-based genetic sequencing for von Willebrand disease
Background: von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder with a wide spectrum of causative variants. Next-generation sequencing analyzes the entire VWF gene and provides concomitant assessment of other genes, allowing differentiation between genocopies. Objectives:...
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Elsevier
2025-02-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2475037925000548 |
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| author | Radha Ramanan Christine Van Laer Sarissa Baert Cyrielle Kint Chris Van Geet Quentin Van Thillo Peter Verhamme Thomas Vanassche James D. McFadyen Andrew C. Perkins Huyen A. Tran Veerle Labarque Kathleen Freson |
| author_facet | Radha Ramanan Christine Van Laer Sarissa Baert Cyrielle Kint Chris Van Geet Quentin Van Thillo Peter Verhamme Thomas Vanassche James D. McFadyen Andrew C. Perkins Huyen A. Tran Veerle Labarque Kathleen Freson |
| author_sort | Radha Ramanan |
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| description | Background: von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder with a wide spectrum of causative variants. Next-generation sequencing analyzes the entire VWF gene and provides concomitant assessment of other genes, allowing differentiation between genocopies. Objectives: We aimed to assess the clinical impact of panel-based sequencing in all VWD patients sequenced at UZ Leuven. Methods: We conducted a single-center retrospective study of all patients with confirmed or suspected VWD who were screened with panel-based whole-exome sequencing. Presequencing diagnosis was performed using laboratory measures of VWF activity and quantity. Postsequencing diagnosis was informed by variant curation in combination with laboratory measures. We measured clinically meaningful changes in the pre- vs postgenetic sequencing diagnosis and subtyping. Results: The study included 108 patients. The population was predominantly composed of pediatric patients <18 years old (77/108; 71%) and females (66/108; 61%). The largest presequencing subgroup was those with low VWF (61/108; 56%), followed by type 1 VWD (21/108; 19%) and type 2 not otherwise specified (18/108; 17%). A clinically meaningful change in management occurred in 19% (20/108) of the study population. The largest effect was seen in the presequencing type 2 group (16/24; 67%). In the type 2 group who could not be accurately subtyped into 2A/B/M/N prior to sequencing (type 2 not otherwise specified), 15/18 (83%) were able to be subtyped or given a different diagnosis postsequencing. Conclusion: Panel-based sequencing for VWD in a well-selected cohort, particularly those with type 2 and type 3 VWD, was clinically relevant in differentiating genocopies, directing therapies, and family planning. Sequencing in those with low VWF and type 1 VWD rarely changed management. |
| format | Article |
| id | doaj-art-e26fe0857a0f4838aaf817424ec84fbb |
| institution | OA Journals |
| issn | 2475-0379 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
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| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj-art-e26fe0857a0f4838aaf817424ec84fbb2025-08-20T02:12:03ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792025-02-019210273010.1016/j.rpth.2025.102730Clinical utility of panel-based genetic sequencing for von Willebrand diseaseRadha Ramanan0Christine Van Laer1Sarissa Baert2Cyrielle Kint3Chris Van Geet4Quentin Van Thillo5Peter Verhamme6Thomas Vanassche7James D. McFadyen8Andrew C. Perkins9Huyen A. Tran10Veerle Labarque11Kathleen Freson12Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; Australian Centre for Blood Diseases, Monash University, Melbourne, Australia; Ronald Sawers Haemophilia Treatment Centre, Alfred Hospital, Melbourne, Australia; Department of Human Molecular Pathology, Alfred Hospital, Melbourne, AustraliaDepartment of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; Clinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, BelgiumCentre for Human Genetics, University Hospitals Leuven, Leuven, BelgiumCentre for Human Genetics, University Hospitals Leuven, Leuven, BelgiumDepartment of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; Department of Paediatrics, Paediatric Haematology and Oncology, University Hospitals Leuven, Leuven, BelgiumDepartment of Vascular Medicine and Haemostasis, University Hospitals Leuven, Leuven, BelgiumDepartment of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; Department of Vascular Medicine and Haemostasis, University Hospitals Leuven, Leuven, BelgiumDepartment of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; Department of Vascular Medicine and Haemostasis, University Hospitals Leuven, Leuven, BelgiumAustralian Centre for Blood Diseases, Monash University, Melbourne, Australia; Ronald Sawers Haemophilia Treatment Centre, Alfred Hospital, Melbourne, AustraliaAustralian Centre for Blood Diseases, Monash University, Melbourne, Australia; Department of Human Molecular Pathology, Alfred Hospital, Melbourne, AustraliaAustralian Centre for Blood Diseases, Monash University, Melbourne, Australia; Ronald Sawers Haemophilia Treatment Centre, Alfred Hospital, Melbourne, AustraliaDepartment of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; Department of Paediatrics, Paediatric Haematology and Oncology, University Hospitals Leuven, Leuven, BelgiumDepartment of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium; Correspondence Kathleen Freson, Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.Background: von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder with a wide spectrum of causative variants. Next-generation sequencing analyzes the entire VWF gene and provides concomitant assessment of other genes, allowing differentiation between genocopies. Objectives: We aimed to assess the clinical impact of panel-based sequencing in all VWD patients sequenced at UZ Leuven. Methods: We conducted a single-center retrospective study of all patients with confirmed or suspected VWD who were screened with panel-based whole-exome sequencing. Presequencing diagnosis was performed using laboratory measures of VWF activity and quantity. Postsequencing diagnosis was informed by variant curation in combination with laboratory measures. We measured clinically meaningful changes in the pre- vs postgenetic sequencing diagnosis and subtyping. Results: The study included 108 patients. The population was predominantly composed of pediatric patients <18 years old (77/108; 71%) and females (66/108; 61%). The largest presequencing subgroup was those with low VWF (61/108; 56%), followed by type 1 VWD (21/108; 19%) and type 2 not otherwise specified (18/108; 17%). A clinically meaningful change in management occurred in 19% (20/108) of the study population. The largest effect was seen in the presequencing type 2 group (16/24; 67%). In the type 2 group who could not be accurately subtyped into 2A/B/M/N prior to sequencing (type 2 not otherwise specified), 15/18 (83%) were able to be subtyped or given a different diagnosis postsequencing. Conclusion: Panel-based sequencing for VWD in a well-selected cohort, particularly those with type 2 and type 3 VWD, was clinically relevant in differentiating genocopies, directing therapies, and family planning. Sequencing in those with low VWF and type 1 VWD rarely changed management.http://www.sciencedirect.com/science/article/pii/S2475037925000548genotypehigh-throughput nucleotide sequencingphenotypevon Willebrand diseases |
| spellingShingle | Radha Ramanan Christine Van Laer Sarissa Baert Cyrielle Kint Chris Van Geet Quentin Van Thillo Peter Verhamme Thomas Vanassche James D. McFadyen Andrew C. Perkins Huyen A. Tran Veerle Labarque Kathleen Freson Clinical utility of panel-based genetic sequencing for von Willebrand disease Research and Practice in Thrombosis and Haemostasis genotype high-throughput nucleotide sequencing phenotype von Willebrand diseases |
| title | Clinical utility of panel-based genetic sequencing for von Willebrand disease |
| title_full | Clinical utility of panel-based genetic sequencing for von Willebrand disease |
| title_fullStr | Clinical utility of panel-based genetic sequencing for von Willebrand disease |
| title_full_unstemmed | Clinical utility of panel-based genetic sequencing for von Willebrand disease |
| title_short | Clinical utility of panel-based genetic sequencing for von Willebrand disease |
| title_sort | clinical utility of panel based genetic sequencing for von willebrand disease |
| topic | genotype high-throughput nucleotide sequencing phenotype von Willebrand diseases |
| url | http://www.sciencedirect.com/science/article/pii/S2475037925000548 |
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