A COMMON LARGE DELETION OF VWF IN GERMAN AND ITALIAN PATIENTS WITH SEVERE VON WILLEBRAND DISEASE TYPE 3
Abstract number: O-W-065
Schneppenheim1 R., Castaman2 G., Federici3 A.B., Franchini4 M., Kreuz5 W., Marschalek6 R., Obser1 T., Oldenburg7 J., Oyen1 F., Budde8 U.
11Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 22Department of Hematology and Hemophilia and Thrombosis Center, San Bortolo Hospital, Vicenza 33Angelo Bianchi Bonomi Hemophilia Thrombosis Center, Department of Internal Medicine, University of Milan, Milan 44Hemophilia and Blood Transfusion Center, Hospital of Verona, Verona, Italy 55Department of Pediatric Hematology, Oncology, and Hemostaseology, University Children's Hospital 66Institute of Pharmaceutical Biology/ZAFES/DCAL, Johann-Wolfgang-Goethe-University Frankfurt, Frankfurt 77Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn 88Coagulation Laboratory, Lab Association Prof. Arndt and Partners, Hamburg, Germany
How-to-cite Schneppenheim R, Castaman G, Federici AB, Franchini M, Kreuz W, Marschalek R, Obser T, Oldenburg J, Oyen F, Budde U. A COMMON LARGE DELETION OF VWF IN GERMAN AND ITALIAN PATIENTS WITH SEVERE VON WILLEBRAND DISEASE TYPE 3. J Thromb Haemost 2007; 5 Supplement 2: O-W-065
Abstract
Introduction: Severe von Willebrand disease type 3 is caused by large deletions, insertions, small truncating mutations, splice site mutations and missense mutations of the gene, respectively. Large deletions have been regarded as being a rare cause of the complete lack of VWF, and complete deletions of the gene have only been identified in Italian and German patients to date (1, 2, 3). However, their extents and their breakpoints have not been determined until now.
Methods: We carried out deletion mapping by PCR and primer walking of a large homozygous deletion identified in a German patient with VWD type 3 and a VWF inhibitor and developed a deletion specific PCR to facilitate screening of additional patients. Haplotype analysis was carried out to study the genetic background of the deletions.
Results: The centromeric breakpoint of the deletion is located between VWF and the adjacent CD9 gene, the telomeric breakpoint in intron 3 of the VWF adjacent Transmembrane Protein 16 B gene (TMEM16B), respectively, comprising about 253 kb of genomic sequence (del253k). We identified the same deletion in the heterozygous state in the 2nd German patient who is a compound heterozygote for del253k and 3605delC, in two additional unrelated homozygous index patients from Italy, and in another Italian patient being compound heterozygous for del253k and C2671Y. All but the latter patient had inhibitors aginst VWF. Haplotype analysis suggests a common genetic background of del253k.
Conclusions: In silico analysis suggests DNA double strand breaks and subsequent non-homologous end-joining repair as the likely deletion mechanism. Homozygosity for del253k in non-consanguineous families from two different countries suggests that large deletions causing VWD type 3 might be more common as previously thought. Our deletion specific assay now allows a simple and rapid detection even of heterozygous patients and carriers.
References: 1) Shelton-Inloes et al. J Clin Invest 1987; 2) Ngo et al. PNAS 1988; 3) Schneppenheim et al. Hum Genet. 1994
