Clinical utility of panel-based genetic sequencing for von Willebrand disease

Abstract

Introduction

Von Willebrand disease (VWD) is the most prevalent inherited bleeding disorder with a wide spectrum of causative variants. Next-generation sequencing (NGS) analyses the entire VWF gene and provides concomitant assessment of other genes allowing differentiation between genocopies.

Methods

We conducted a single-centre retrospective study of all patients with confirmed or suspected VWD who were screened with panel-based whole-exome sequencing (WES) for inherited bleeding disorders. Pre-sequencing diagnosis was performed using laboratory measures of VWF activity and quantity. Post-sequencing diagnosis was informed by variant curation in combination with laboratory measures. We measured clinically meaningful changes in the pre- vs post-genetic sequencing diagnosis and subtyping.

Results

The study included 108 patients. The population was predominantly composed of paediatric patients < 18 years old (77/108, 71%) and females (66/108, 61%). The largest pre-sequencing subgroup was those with low VWF (n=61, 56%), followed by type 1 VWD (n=21, 19%) and type 2 not otherwise specified (NOS) (n=18, 17%). A clinically meaningful change in management occurred in 19% (20/108) of the study population. The largest effect was seen in the pre-sequencing type 2 group (67%, 16/24). In the type 2 group who could not be accurately subtyped into 2A/B/M/N prior to sequencing (type 2 NOS), 15/18 (83%) were able to be subtyped or given a different diagnosis post sequencing.

Conclusion

Panel-based sequencing for VWD in a well-selected cohort, particularly those with type 2 and type 3 VWD, was clinically relevant in differentiating genocopies, directing therapies and family planning. Sequencing in those with low VWF and type 1 VWD rarely changed management.