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Inherited thrombocytopenia’s (IT) are characterised by low platelet counts and bleeding tendencies in affected individuals. Diagnosis of IT is important to guide treatment, inform prognosis and provide genetic counseling. Unfortunately, standard testing methods that interrogate platelet function and structure lack sensitivity, specificity and standardisation. This thesis developed and employed a next generation sequencing (NGS) platform for the diagnosis of IT and explored mechanisms underpinning IT through laboratory investigation of novel variants detected through this method. NGS was performed for approximately 120 patients and identified pathogenic variants in a significant fraction. Most pathogenic variants were detected in the MYH9 gene (12.4% of the cohort) and included the description of a novel variant (W828R). Novel variants were also detected in transcription factors FLI1, GFI1B and RUNX1. Disease modelling experiments of novel variants confirmed their pathogenicity and in the case of the novel homozygous FLI1 variant (R324W), analysis consolidated knowledge of the aetiology of thrombocytopenia in patients with Paris-Trousseau syndrome. Acquisition of molecular data provided opportunity to assess diagnostic algorithms. We demonstrated the potential of mean platelet diameter measurements to streamline diagnostic algorithms and aid in initial classification of patients with IT. Finally, we performed disease modelling of GFI1B-RT to show that the clinical phenotype of GFI1B variants is dependent on the site disrupted by, and nature of, the GFI1B mutation. We show that GFI1B regulates the CD34 promoter and that transcriptional deregulation induced by mutant GFI1B underlies persistent platelet CD34 expression common to GFI1B variants. We conclude that a an approach using NGS is an effective diagnostic tool to examine IT and that data generated by molecular analysis provides a foundation to explore mechanisms of disease, and improve diagnostic algorithms.