Identification and functional investigation of genes involved in inherited bleeding disorders

Maclachlan, Annabel Elizabeth Nicol (2020). Identification and functional investigation of genes involved in inherited bleeding disorders. University of Birmingham. Ph.D.

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Inherited bleeding disorders are a heterogeneous group of conditions that reflect abnormalities of the vascular endothelium, coagulation factor proteins and platelets. Clinical diagnosis is often challenging despite patients having extensive bleeding histories and 60% of patients recruited to the Genotyping and Phenotyping of Platelets (GAPP) study remain undiagnosed. A novel assay was trialled in 71 affected patients to investigate platelet spreading ability. This identified patients with abnormal platelet area and circularity who were negative for defects in aggregation and revealed that this assay could identify platelet morphological defects that might be missed by lumi-aggregometry alone. In addition, whole exome sequencing was employed in 10 unrelated families in this undiagnosed patient cohort. The definitive genetic cause of disease was identified in 1 of these families, a missense variant in THBD, with several plausible candidate variants remaining for the other families. In 2 of these families, and a further family from the GAPP study cohort, novel and rare genetic variants in TTLL10 were identified. The protein tubulin tyrosine ligase-like 10 (TTLL10) shows a potential role in the post translational modification of tubulin microtubules in platelets thereby affecting normal platelet physiological processes. In conclusion, genetic variants identified in genes not previously known to cause bleeding could lead to further understanding of haemostasis and thrombosis following subsequent functional studies.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Licence: All rights reserved
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cardiovascular Sciences
Funders: British Heart Foundation
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine


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