OC 78.2 - Whole exome sequencing in patients with rare bleeding disorders: data from the RBiN study

Wednesday, July 13, 2022

10:30 AM – 10:45 AM

Location: ExCel Center, ICC Capital Suite Room 1

Presentation Format: In-Person

Presenting Author(s)

Sterre Willems, Msc

PhD Candidate, resident internal medicine
Radboud university medical center, Hemophilia Treatment Center, Nijmegen – Eindhoven – Maastricht
Nijmegen, Gelderland, Netherlands

Co-Author(s)

JS

Joline L. Saes

Resident internal medicine - hematology
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands
Nijmegen, Gelderland, Netherlands
AS

Annet Simons

Clinical Laboratory Geneticist
Department of Human Genetics, Radboud university medical center
Nijmegen, Gelderland, Netherlands
MW

Marjan Weiss

Clinical Laboratory Geneticist
Department of Human Genetics, Radboud university medical center
Nijmegen, Gelderland, Netherlands
Karina Meijer, MD, PhD

MD, PhD, Internist-haematologist, Professor
Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Groningen, Groningen, Netherlands
MC

Marjon H. Cnossen

Associate professor, pediatric hematologist, MD, PhD
Department of Pediatric Hematology, Erasmus MC – Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands
Rotterdam, Zuid-Holland, Netherlands
Roger E.G. Schutgens, MD, PhD, MSc

Internist-hematologist, Professor
Center for Benign Hematology, Thrombosis and Hemostasis, Van Creveldkliniek, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands
Utrecht, Utrecht, Netherlands
MP

Marjolein Peters

Pediatric hematologist
Department of Pediatric Hematology, Amsterdam University Medical Centers, location Emma Children’s Hospital, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
LN

Laurens Nieuwenhuizen

Internist-hematologist
Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands. Department of Hematology, Maxima Medical Center, Eindhoven, The Netherlands.
Eindhoven, Noord-Brabant, Netherlands
PD

Paul L. Den Exter, MD, PhD

Internist – Vascular Medicine Specialist
Leiden University Medical Center
Leiden, Zuid-Holland, Netherlands
IK

Ilmar C. Kruis

Representative
Netherlands Hemophilia Society, Nijkerk, The Netherlands
Nijkerk, Gelderland, Netherlands
NB

Nicole M.A. Blijlevens

Internist-hematologist, Professor
Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands
Nijmegen, Gelderland, Netherlands
Wv

Waander L. van Heerde

Biochemist, Coagulation Physiologist, Chief Scientific Officer Enzyre BV
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands. Enzyre BV, Novio Tech Campus, Nijmegen, The Netherlands.
Nijmegen, Gelderland, Netherlands
SS

Saskia E.M. Schols

Internist-hematologist
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands
Nijmegen, Gelderland, Netherlands

Background: Rare bleeding disorders (RBD) encompass a heterogenous group of rare coagulation factor deficiencies and disorders of fibrinolysis. Little is known about the genetic background, especially in patients with mild bleeding disorders.

Aims: To improve understanding in genetic variants and investigate the role for whole exome sequencing (WES) in the diagnostics of RBD.

Methods: The Rare Bleeding Disorders in The Netherlands (RBiN) study is a nation-wide cross-sectional multicenter study, which was conducted between November 2017 and February 2019 among patients with a hereditary RBD from all six Dutch Hemophilia Treatment Centers. WES was conducted with genomic DNA of included patients after informed consent; a selected gene panel was used including 156 genes proven to be involved in thrombosis and hemostasis. Variants with allele frequencies above 1% were not included.

Results: WES results were available for 156 of the 263 included patients; 46 patients had severe factor deficiency. In 119 (76%) patients, a disease-causing class 4/5 genetic variant was found. These cases were considered solved (Table). In 34 patients of the solved cases group, additional pathogenic variants (class 3, 4 or 5) were found in other genes. Homozygous or compound heterozygous variants were found in 21 (14%) patients, all with severe coagulation factor deficiency. Moreover, 26 patients (19 with severe factor deficiency) had two variants in one gene, although unknown whether in cis or trans configuration. An additional number of 14 (9%) patients had a genetic variant that was likely or possibly causative of their RBD. No disease-causing pathogenic genetic variants were found in patients with PA1-1 deficiency or hyperfibrinolysis.

Conclusion(s): The diagnostic yield of WES in patients with RBD is high, with the exception of patients with hyperfibrinolysis and PAI-1 deficiency. In 24% of RBD patients, bleeding phenotype may be explained by the interplay of pathogenic variants in multiple hemostasis genes and needs further attention.