PB0954 - Co-occurrence of extremely rare ENG S484S and V504M variants in two independent women with unexplained venous thrombosis.

Monday, June 24, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

David-Alexandre Trégouët

Senior Investigator
Bordeaux Population Health research Center, Inserm U1219, Bordeaux University
Bordeaux, Aquitaine, France

Co-Author(s)

OS

Omar Soukarieh

Post Doctoral Fellow
INSERM U1034, Pessac
Bordeaux, Aquitaine, France
MG

Marine Germain

Research Scientist
University of Bordeaux
Bordeaux, Aquitaine, France
NS

Noémie Saut

Research Assistant
C2VN, INRAE, INSERM Aix-Marseille University, Marseille, France,
Marseille, Provence-Alpes-Cote d'Azur, France
JD

Jean-François Deleuze

Director
CNRGH, CEA, France
Evry, Ile-de-France, France
Pierre Suchon

Clinial Research Investigator
C2VN, INRAE, INSERM Aix-Marseille University, Marseille, France,
Marseille, Provence-Alpes-Cote d'Azur, France
Pierre Morange, MD, PhD

Aix-Marseille University, France

Background: There is accumulating evidence supporting the role of the soluble form of Endoglin in platelets biology including thrombosis. However, little is known about the possible link between rare ENG variants and venous thrombosis (VT).

Aims: To investigate the contribution of rare ENG genetic variations in VT risk.

Methods: We scrutinized the whole-genome sequence data of a sample of 200 independent VT patients of European ancestry and free of any thrombophilia defects for the presence of rare (minor allele frequency < 0.5% in GnomAD_V4 population) coding ENG variants. Identified candidates were looked in an independent sample of 198 VT women.

Results: Seven rare coding ENG variants (3 missense/4 synonymous) were identified in the discovery sample. Noteworthy missense variant include the NM_001114753.3 c.1342C>T in exon 11 identified in a woman with VT at 38yo and predicted to skip the first 42 nucleotides of the exon; the c.1904C>T (S635L) variant in the last exon, identified in a man with VT at 69yrs and predicted to be deleterious by several bioinformatics scores; the c.1510G>A (V504M) in exon 12 and identified in a woman with VT at 10yo. Interestingly, this patient was also heterozygote for the rare c.1452C>T (S484S) synonymous variant also in exon 12 and predicted to simultaneously skip the 39 first nucleotides of exon 12 or to alter splicing regulators suggesting the skipping of the entire exon (Table). In the replication sample, the co-occurrence in cis of the S484S and V504M variants was detected in a woman with VT at 31yo.
Experimental works are ongoing to validate the bioinformatics predictions and to investigate whether the S484S and/or V504M variations could be pro-thrombotic.

Conclusion(s): Confirming these findings within extensive genomic biobanks would suggest the merit of incorporating ENG into the tier1 genes panel for VT and would also furnish novel molecular evidence for Endoglin’s role in thrombosis.