Bleeding, Thrombotic and Platelet Disorders (BPD)

BackgroundPeople Panel D_2x3_Rare Diseases

Rare inherited bleeding disorders are the commonest cause of predominant mucocutaneous bleeding. The molecular causes of this group of disorders can be broadly categorised in abnormalities of plasma coagulation, the formation and function of platelets and impaired vessel wall integrity. Current biochemical, coagulation factor and platelet function tests for patients presenting with a personal or family history of excessive bleeding or low platelet counts are labour intensive and ultimately inadequate in the majority of cases. The immediate purpose of this study is to replace the current plethora of tests by a single next generation sequencing (NGS)-based one.

For this to happen the following steps have to be made:

  1. Identify the genetic basis of hitherto unresolved bleeding, thrombotic and particularly platelet disorders by exome-sequencing (WES) or Whole Genome Sequencing (WGS)
  2. Curate known and still to be discovered clinically relevant sequence variants in Locus Reference Genomic (LRG), thus creating a universal and static reference to enable clinical diagnosis from NGS sequence
  3. Develop and validate a sequence capture assay for the sensitive and specific detection of clinically relevant variants in at least 150 causative genes

Funding has been secured for 2 and 3 as well as WGS capacity for 1250 samples with the purpose of identifying novel genes.

Recruitment Criteria:

  1. Any bleeding disorder of unknown molecular aetiology
  2. Abnormal platelet count, volume, morphology and/or function
  3. Any combination of 1 and 2

Cases will be ascertained for family history so that the expected mode of inheritance can inform the statistical analysis. Clinical phenotypic information already captured will be coded using Human Phenotype Ontology {Clin Genet. 2010 Jun;77(6):525-34} terms enabling richer grouping of related conditions, and thus improving power. If there is credible evidence of de novo mutations then we may seek to ascertain this through sequencing of both parents.

Centres at which BPD is recruiting:

Cambridge University Hospitals NHS Foundation Trust
Bart’s Health NHS Trust, London
Cardiff & Vale UHB
Central Manchester University Hospital NHS Foundation Trust
East Kent Hospitals University NHS Foundation Trust
Great Ormond Street Hospital for Children NHS Foundation Trust,
Guy’s & St Thomas’ NHS Foundation Trust,
Hampshire Hospitals NHS Foundation Trust,
Hull & East Yorkshire Hospitals NHS Foundation Trust
Imperial College Healthcare NHS Trust,
Leeds Teaching Hospitals NHS Trust, Leeds Children’s Hospital
Newcastle upon Tyne Hospitals NHS Foundation Trust

NHS Grampian, Aberdeen Royal Infirmary
NHS Greater Glasgow and Clyde: Glasgow Royal Infirmary, Royal Hospital for Children
Oxford University Hospitals NHS Foundation Trust
Papworth Hospital NHS Foundation Trust,
Royal Free London NHS Foundation Trust, London
Royal Liverpool & Broadgreen University Hospitals NHS Trust
Salisbury NHS Foundation Trust
Sheffield Children’s Hospital NHS Foundation Trust
Sheffield Teaching Hospitals NHS Foundation Trust
University College London Hospitals NHS Foundation Trust
University Hospital Southampton NHS Foundation Trust

University Hospitals Bristol NHS Foundation Trust
*Alder Hey, Liverpool Children’s (in progress)
*NHS Lothian, Edinburgh (in progress)

Professor Willem Ouwehand
Professor Mike Laffan
Professor Chris van Geet

If you feel your NHS site would be suitable to recruit for BPD, or for the full details of Recruitment Criteria, please get in contact with the BPD Study Coordinator Dr Sofia Papadia