Application of whole-exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


Rare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty-seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five-tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work-up of IBD is of great benefit.


Enheter & grupper
Externa organisationer
  • Copenhagen University Hospital
  • Skåne University Hospital
  • University of Copenhagen

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Hematologi


Sidor (från-till)308-322
TidskriftBritish Journal of Haematology
Tidigt onlinedatum2017
StatusPublished - 2017
Peer review utfördJa