Familial Hypercholesterolaemia (FH) is a common autosomal dominant disorder of the defective plasma clearance of LDL-cholesterol. Mutations in three genes, LDLR/APOB/PCSK9, can be detected in 60-90% of definite FH patients. DNA-based testing for FH mutations has important clinical utility and is recommended by the UK and European guidelines to identify affected relatives. This thesis aimed to determine the frequency and spectrum of FH mutations in two independent cohorts of FH patients (from one Oxford lipid clinic, and of Indian background). The FH mutation spectrum was shown to be highly heterogeneous and the mutation detection rate was significantly dependent on the pre-treatment total cholesterol and triglyceride levels. This project also validated the findings that a proportion of clinically diagnosed FH patients have a polygenic cause of hypercholesterolaemia due to an accumulation of common mild LDL-C-raising alleles by analysing LDL-C gene score in 88 mutation negative and 21 mutation positive FH patients, and by replicating the results in further 231 FH patients. A high-throughput DNA sequencing method was assessed as a novel diagnostic tool for detection of FH mutations, and compared it with the currently used methods. This highlighted the need for updating the current FH mutation screening methods as well as the need for more efficient bioinformatics for the next generation sequencing data analysis. Lastly, whole exome sequencing of 125 definite FH patients with no mutations detected in known genes was performed to identify novel monogenic causes of FH. Variants in two genes, CH25H and INSIG2, were identified as potential novel FH mutations. Overall, the results of this thesis demonstrate the heterogeneous FH aetiology and help to understand the genetic architecture of the disease
