A Baltic Origin of the Common ADAMTS13 Mutation 4143insA

Abstract number: P0849

Schneppenheim¹ R, Kremer Hovinga² JA, Budde³ U, Karpman⁴ D, Brockhaus⁵ W, Korczowski⁶ B, Milosevic⁷ D, Oyen¹ F, von Rosen⁸ J, Tjønnfjord⁹ GE, Pimanda¹⁰ JE, Lämmle² B

¹¹University of Hamburg, Hamburg, Germany ¹¹University of Hamburg, Hamburg, Germany ¹⁰¹⁰ University of Cambridge, Cambridge, UK ²²University Hospital, Inselspital, Bern, Switzerland ³³Coagulation Laboratory, Hamburg, Germany ⁴⁴Department of Pediatrics, Lund University, Lund, Sweden ⁵⁵Klinikum Nürnberg, Nürnberg, Germany ⁶⁶Regional Hospital, University of Rzeszów, Rzeszów, Poland ⁷⁷University Hospital, Zagreb, Croatia ⁸⁸Länssjukhuset Ryhov, Jönköping, Sweden ⁹⁹Rikshospitalet, University Hospital, Oslo, Norway

Severely deficient activity of the von Willebrand Factor (VWF) cleaving metalloprotease, ADAMTS13 is associated with thrombotic thrombocytopenic purpura (TTP). The mutation spectrum of ADAMTS13 is rather heterogeneous and a number of mutations spread across the gene have been described in association with congenital TTP. The 4143insA mutation is unusual with respect to its geographic concentration. Following the initial report from Germany in which the 4143insA mutation was detected in four apparently unrelated families, a further eight patients from Norway, Sweden, Poland, Germany, Australia and Croatia have now been identified. Confirmation that the Australian patient is of German ancestry, together with the Baltic origin of most of the other patients, suggested that the 4143insA mutation has a common genetic background. We established ADAMTS13 haplotypes by analyzing 17 polymorphic intragenic markers. The haplotypes linked to 4143insA were identical in all informative families. Three novel candidate mutations, C347S, P671L and R1060W as well as the known mutation R507Q, were also identified during the course of the study. We conclude that 4143insA has a common genetic background and is frequent among patients with hereditary ADAMTS13 deficiency in countries around the Baltic Sea.