PB0844 - Assessment of the de novo origin of the p.Val1316Met mutation in four unrelated patients with type 2B von Willebrand disease

Monday, June 26, 2023

18:30 – 19:30 ET

Room: Exhibition

Co-Author(s)

Maria Teresa Pagliari

Researcher
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy

Co-Author(s)

Luciano Baronciani

Biologist
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy
GC

Giovanna Cozzi

Biologist
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy
PC

Paola Colpani

Lab. Technician
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy
Milan, Lombardia, Italy
CC

Cristina Curcio

Biologist
Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Milan, Lombardia, Italy
SS

Simona Maria Siboni

Hematologist
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Milan, Lombardia, Italy

Presenting Author(s)

Flora Peyvandi, MD, PhD (she/her/hers)

Director
IRCCS Ca' Granda Maggiore Hospital Foundation, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy; Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milano, Italy
Milano, Lombardia, Italy

Background: The assessment of personal and family bleeding history is an established criterion for the diagnosis of von Willebrand disease (VWD), a common inherited bleeding disorder. In particular, type 2B VWD includes variants with an increased affinity for glycoprotein (GP)Ib and is inherited with a dominant pattern. Among these, the p.Val1316Met mutation is one of the most frequently described. To date, little information is available regarding the proportion of de novo variants in patients with VWD.

Aims: To investigate the origin of the p.Val1316Met identified in four type 2B patients referred to our Center.

Methods: Conventional phenotype tests were used to evaluate patient plasma, as recommended by the ISTH-SSC guidelines. Direct sequencing of exon 28 was performed using Sanger method. Short tandem repeats (STR) I and STRII in intron 40 were performed using labelled primers and analyzed using GENEMAPPER Software.

Results: Biochemical and molecular data for probands and available family members are reported in Table 1. Each proband had a different STRI-STRII set. The STRI-STRII sets identified in probands I and II were derived by the respective parents, despite the absence of the pathogenic mutation in these latter. This information was not obtained for probands III and IV (unavailable parents’ samples).

Conclusion(s): The finding of p.Val1316Met mutation in two unrelated subjects (probands I and II), in absence of a family history of bleeding, suggests that the mutation has arisen from two independent de novo events. This may be explained by the presence of a CpG dinucleotide at codon 1316, as CpG dinucleotides are known to have a high mutation rate. The identification of different STRI-STRII sets in the four probands suggests that p.Val1316Met is the result of independent events in these families further supporting the hotspot mechanism for this mutation.