ISTH Congress Abstracts

Official abstracts site for the ISTH Congress

MENU 

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

1Radboud university medical center, Nijmegen, The Netherlands; , Nijmegen, Gelderland, Netherlands, 2Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, The Netherland, Nijmegen, Gelderland, Netherlands, 3Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, The Netherlands, Nijmegen, Gelderland, Netherlands, 4University Medical Center Groningen, Groningen, Groningen, Netherlands, 5Department of Pediatric Hematology, Sophia Children’s Hospital, Erasmus University Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands, Rotterdam, Zuid-Holland, Netherlands, 6University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, Utrecht, Utrecht, Netherlands, 7Department of Pediatric Hematology, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands, Utrecht, Utrecht, Netherlands, 8Department of Hematology, Máxima Medical Center, Eindhoven, Netherlands; Radboud university medical center, Hemophilia Treatment Center, Nijmegen – Eindhoven – Maastricht, Netherlands, Eindhoven, Noord-Brabant, Netherlands, 9Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands, 10Netherlands Hemophilia Society, Nijkerk, Netherlands, Nijkerk, Gelderland, Netherlands, 11Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands, Nijmegen, Gelderland, Netherlands, 12Department 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, 13Department of Hematology, Radboud university medical center, Nijmegen, the Netherlands; Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, the Netherlands, Nijmegen, Gelderland, Netherlands

Abstract Number: OC 78.2

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Rare Bleeding Disorders

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.

Table

Table 1: Overview of the number of patients in each RBD and yield of whole exome sequencing. A case was considered ‘solved’ if the genetic variant confirmed the diagnosis of the RBD in question.
* Baseline coagulation factor level was used. If not available, the centrally measured coagulation factor level was used.
** Euglobulin clot lysis time ratio was used for patients with hyperfibrinolysis.

To cite this abstract in AMA style:

Willems S, Saes J, Simons A, Weiss J, Meijer K, Cnossen M, Schutgens R, Peters M, Nieuwenhuizen L, Den Exter P, Kruis I, Blijlevens N, van Heerde W, Schols S. Whole exome sequencing in patients with rare bleeding disorders: data from the RBiN study [abstract]. https://abstracts.isth.org/abstract/whole-exome-sequencing-in-patients-with-rare-bleeding-disorders-data-from-the-rbin-study/. Accessed September 21, 2023.

« Back to ISTH 2022 Congress

ISTH Congress Abstracts - https://abstracts.isth.org/abstract/whole-exome-sequencing-in-patients-with-rare-bleeding-disorders-data-from-the-rbin-study/