INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. Few studies have explored the molecular basis of type 2 VWD. AIM: This study aimed to identify variants associated with type 2 VWD. METHODS: We collected clinical and laboratory data, as well as response to desmopressin and bleeding assessment tool (BAT) score in patients diagnosed with type 2 VWD. We sequenced exons 17, 18, 20 and 28 of the VWF gene. RESULTS: We identified 19 different variants in 40 unrelated patients (47.5%). Most of the variants (84.2%) were found in exon 28. A total of 10/19 variants (52.6%) were identified as "likely causative" in 17/40 patients (42.5%), according to the ISTH-SSC and EAHAD VWF gene mutations databases. Nine variants were initially identified as potentially benign. However, through analyses in silico, four of these variants were reclassified as "likely pathogenic" (Ile1380Val, Asn1435Ser, Ser1486Leu and Tyr1584Cys). Response to desmopressin was associated with three variants: Met740Ile, Arg1597Gln and Tyr1584Cys. Major bleeding was associated with variants related to VWD subtypes 2B and 2M. CONCLUSION: In conclusion, we identified 19 variants, of which 14 are "likely pathogenic" and therefore associated with VWD. We suggest a possible association of pathogenic variants with major bleeding, response to desmopressin and BAT score ≥10, although this requires further confirmation.
INTRODUCTION:von Willebrand disease (VWD) is the most common inherited bleeding disorder. Few studies have explored the molecular basis of type 2 VWD. AIM: This study aimed to identify variants associated with type 2 VWD. METHODS: We collected clinical and laboratory data, as well as response to desmopressin and bleeding assessment tool (BAT) score in patients diagnosed with type 2 VWD. We sequenced exons 17, 18, 20 and 28 of the VWF gene. RESULTS: We identified 19 different variants in 40 unrelated patients (47.5%). Most of the variants (84.2%) were found in exon 28. A total of 10/19 variants (52.6%) were identified as "likely causative" in 17/40 patients (42.5%), according to the ISTH-SSC and EAHAD VWF gene mutations databases. Nine variants were initially identified as potentially benign. However, through analyses in silico, four of these variants were reclassified as "likely pathogenic" (Ile1380Val, Asn1435Ser, Ser1486Leu and Tyr1584Cys). Response to desmopressin was associated with three variants: Met740Ile, Arg1597Gln and Tyr1584Cys. Major bleeding was associated with variants related to VWD subtypes 2B and 2M. CONCLUSION: In conclusion, we identified 19 variants, of which 14 are "likely pathogenic" and therefore associated with VWD. We suggest a possible association of pathogenic variants with major bleeding, response to desmopressin and BAT score ≥10, although this requires further confirmation.
Authors: Paula D James; Nathan T Connell; Barbara Ameer; Jorge Di Paola; Jeroen Eikenboom; Nicolas Giraud; Sandra Haberichter; Vicki Jacobs-Pratt; Barbara Konkle; Claire McLintock; Simon McRae; Robert R Montgomery; James S O'Donnell; Nikole Scappe; Robert Sidonio; Veronica H Flood; Nedaa Husainat; Mohamad A Kalot; Reem A Mustafa Journal: Blood Adv Date: 2021-01-12
Authors: Steven Bell; Andreas S Rigas; Magnus K Magnusson; Egil Ferkingstad; Elias Allara; Gyda Bjornsdottir; Anna Ramond; Erik Sørensen; Gisli H Halldorsson; Dirk S Paul; Kristoffer S Burgdorf; Hannes P Eggertsson; Joanna M M Howson; Lise W Thørner; Snaedis Kristmundsdottir; William J Astle; Christian Erikstrup; Jon K Sigurdsson; Dragana Vuckovic; Khoa M Dinh; Vinicius Tragante; Praveen Surendran; Ole B Pedersen; Brynjar Vidarsson; Tao Jiang; Helene M Paarup; Pall T Onundarson; Parsa Akbari; Kaspar R Nielsen; Sigrun H Lund; Kristinn Juliusson; Magnus I Magnusson; Michael L Frigge; Asmundur Oddsson; Isleifur Olafsson; Stephen Kaptoge; Henrik Hjalgrim; Gudmundur Runarsson; Angela M Wood; Ingileif Jonsdottir; Thomas F Hansen; Olof Sigurdardottir; Hreinn Stefansson; David Rye; James E Peters; David Westergaard; Hilma Holm; Nicole Soranzo; Karina Banasik; Gudmar Thorleifsson; Willem H Ouwehand; Unnur Thorsteinsdottir; David J Roberts; Patrick Sulem; Adam S Butterworth; Daniel F Gudbjartsson; John Danesh; Søren Brunak; Emanuele Di Angelantonio; Henrik Ullum; Kari Stefansson Journal: Commun Biol Date: 2021-02-03