Molecular genetic investigation into inherited thrombocytopenia

Johnson, Ben David (2017). Molecular genetic investigation into inherited thrombocytopenia. University of Birmingham. Ph.D.

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Inherited thrombocytopenias are a heterogeneous group of disorders characterised by abnormally low platelet counts, often with secondary qualitative defects in platelet function, which can be associated with abnormal bleeding. Next generation sequencing has only previously been employed in small-scale studies and for the confirmation of suspected variants. This study presents the first large-scale approach to fully categorise inherited thrombocytopenia. Ninety-five patients were recruited to the UK-Genotyping and Phenotyping (GAPP) study with inherited thrombocytopenia of unknown genetic aetiology. An average platelet count of 88x109/L was observed across all individuals. Platelet function testing revealed a secondary phenotypic defect in addition to the reduction in platelet count in 71% (61/86). Of the 95 patients, 69 patients, encompassing 47 index cases, were analysed by whole exome sequencing. A variant with a positive prediction of pathogenicity was identified in 40% (19/47) of patients and overall plausible candidate variants of disease were identified in 69% of index cases. Subsequently an inherited thrombocytopenia specific gene panel was developed to serve as a pre-screen for patients prior to whole exome sequencing. In total, candidate variants in genes previously known to be implicated with disease were identified in 77% (20/26) of patients analysed. In conclusion, the application of a combined phenotyping and genotyping approach to patients with inherited thrombocytopenia is an effective and efficient means of complete diagnosis. It also has the added benefit of identifying novel candidate variants in genes not previously known to cause disease that may further our understanding of the processes surrounding haemostasis through subsequent functional studies.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cardiovascular Sciences
Funders: Other
Other Funders: The University of Birmingham
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)


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