Understanding the genetic basis of rare inherited bleeding and platelet disorders: the utility of next-generation sequencing

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Title: Understanding the genetic basis of rare inherited bleeding and platelet disorders: the utility of next-generation sequencing
Authors: Lentaigne, Claire
Item Type: Thesis or dissertation
Abstract: Inherited bleeding and platelet disorders (BPD) are rare, heterogeneous and rarely receive a specific genetic diagnosis. The BRIDGE-Bleeding and platelet disorders consortium was set up to address this using high-throughput sequencing (HTS). More than one thousand probands with inherited BPD of unknown aetiology were recruited to an international consortium study with two over-arching aims: to identify novel genetic loci involved in BPD and provide a better diagnosis for patients. Through applying comprehensive, standardised phenotyping to this large dataset combined with novel analytical methods, several novel candidate genes for BPD have been identified. HTS has also identified variants in known BPD genes, many of them pathogenic, thus providing a diagnosis to many patients with BPD. In this thesis I present the study design and methodology for recruitment and data collection for the BRIDGE-BPD study. I describe the optimisation and application of the Human Phenotype Ontology to phenotype rare BPD and show how this has facilitated gene discovery and improvements in patient diagnosis. In chapters 4 and 5 I show how HTS has identified many variants in known BPD genes and illustrate the challenges faced and methods required for the interpretation of these variants. Many novel candidate BPD genes have also been identified and in chapters 6 and 7 some examples are highlighted with methods for their characterisation. Overall, this thesis demonstrates the utility of HTS in the diagnosis of rare BPD and many of the challenges faced in the interpretation of data from large whole genome sequencing projects and application of this technology to rare diseases.
Content Version: Open Access
Issue Date: Jul-2018
Date Awarded: Nov-2018
URI: http://hdl.handle.net/10044/1/70178
Supervisor: Millar, Carolyn
Laffan, Mike
Funder's Grant Number: P39437
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses

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