PB0282 - Probable additive effect of SNVs on the phenotype of VWD2N patients with p.R816W

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Co-Author(s)

AW

Adriana I. Woods, PhD

Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
Ciudad Autonoma de Buenos Aires, Ciudad Autonoma de Buenos Aires, Argentina
LR

Liliana C. Rossetti

Independent Researcher
Instituto de Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM)
Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
SC

Santiago Castera, Sr.

Biochemist, Ms.
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina
CABA, Ciudad Autonoma de Buenos Aires, Argentina
AB

Alicia N. Blanco

PhD
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina
MC

Maria M. Casinelli

Technician
Department of Hemostasis and Thrombosis, Hematological Research Institute, National Academy of Medicine.
CABA, Ciudad Autonoma de Buenos Aires, Argentina
Cd

Carlos de Brasi, Sr.

Biochemist, PhD
Intituto de Medicina Experimental
CABA, Ciudad Autonoma de Buenos Aires, Argentina
MA

María F. Alberto

Biochemist, PhD
Departamento de Hemostasia y Trombosis, Instituto de Investigaciones Hematologicas, Academia Nacional de Medicina
Ciudad Autonoma de Buenos Aires, Ciudad Autonoma de Buenos Aires, Argentina

Presenting Author(s)

Analia Sánchez-Luceros, MD, PHD

MD, PhD
Departamento de Hemostasia y Trombosis. Academia Nacional de Medicina.
CABA, Ciudad Autonoma de Buenos Aires, Argentina

Background: Type 2N is a rare form of the von Willebrand disease, related to the presence of disease-causing variants (DCVs) located within the FVIII binding site of the VWF, the D’-D3 domains of the VWF-gene. Heterozygotes are considered carriers of the defect(1) and mostly asymptomatic. Homozygotes and compound heterozygotes have clinical and laboratory phenotype frequently mistaken for those of mild hemophilia A.

Aims: Considering that patients heterozygous for VWD2N-p.R816W showed a dominant/severe phenotype(2), we tried to evaluate if there is any association between the co-expression of R816W, their bleeding phenotype, and certain SNVs located in D'-D3 domains in subjects of our region.

Methods: Exons 17 to 27 of VWF gene were amplified by PCR methods and sequenced using Sanger technology. The allelic frequency of five frequent SNVs was compared among controls, VWD2N-p.R816W, and VWD2N-non-p.R816Wpatients: c.2546+25T>C, c.2365A>G p.(T789A), c.2385T>C p.(Y795=), c.2555G>C p.(R852Q), and c.3108+34G>A.
P-value, and OR with confidence interval were calculated. P< 0.05 was considered statistically significant.

Results: VWD2N-p.R816W patients showed a higher frequency of minor alleles of c.2546+25T>C (C-allele), of c.2555G>A p.(R852Q) (A-allele) and of c.3108+34G>A (A-allele) in comparison with both controls and VWD2N-non-p.R816W (table1).The p-values showed a strong significant difference, and the high OR values, a strong association between the co-expression of p.R816W with c.2546+25T>C and c.2555G>A p.(R852Q).
VWD2N-non-p.R816W patients showed a moderate association with c.3108+34G>A.
Regarding the remaining SNVs, VWD2N-non-p.R816W showed a higher OR but the very wide confidence interval reduces its statistical significance with controls (table 2).

Conclusion(s): A strong association between the co-expression of R816W and these SNVs was identified. The presence of c.2546+25T>C, c.2555G>A p.(R852Q), and in minor extent c.3108+34G>A could be considered to have an additive effect contributing to the dominant presentation or severity of the clinical phenotype in VWD2N-pR816W patients. This pattern was not observed in the VWD2N patients with other DVCs.