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The genetics of familial hypercholesterolaemia and establishing familial hypercholeserolaemia genetic testing as a clinical diagnostic service

Heath, Karen Elise; (1999) The genetics of familial hypercholesterolaemia and establishing familial hypercholeserolaemia genetic testing as a clinical diagnostic service. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Familial hypercholesterolaemia (FH) is a monogenically inherited disorder of lipoprotein metabolism caused by a mutation in the low density lipoprotein receptor gene (LDLR). However in a few individuals, the defect lies in the gene for apolipoprotein B (APOB), the ligand for the LDL-receptor, and this is called familial defective apolipoprotein B-100 (FDB), while in others the receptor function is apparently normal and the defect must lie elsewhere. Mutation studies are the most practical way in which one can identify the cause of heterozygous hypercholesterolaemia. A genetic diagnostic service for FH has been established and the various aspects of setting up are described, with unusual cases being reported. The mutations identified are described and mutation detection rates were calculated for groups of paediatric and adult probands from the UK. The feasibility of altemative mutation screening methods and the specificity and sensitivity of reducing the number of tests has been assessed from the results obtained over the last four years. A quantitative fluorescent multiplex PCR screen was adapted to analyse LDLR rearrangements which would improve the genetic diagnosis of FH individuals. One assay based on exons 1, 8, 10, 12 and 16 were optimised and tested on known major rearrangements. A group of FH probands from the USA were then analysed with this multiplex assay. The inter and intra-assay variation were very wide, so a second method was designed to overcome these problems, universal primer quantitative fluorescent multiplex PCR (UPQFM-PCR). The multiplex set developed analysed exons 3, 5, 8, 14, and 17 of LDLR, and the method could also be used to detect major rearrangements in other genes. The method was evaluated by conducting a trial on 15 reported deletions and duplications. Two groups of FH patients from the UK were screened with this UPQFM-PCR assay. The influence of LDLR & APOB mutations on the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin was investigated in patients with heterozygous FH. Data suggest that there may be a difference in cholesterol-lowering between 'severe' and 'mild' LDLR mutations. Future developments and transferring the findings into a clinical genetic service are discussed.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The genetics of familial hypercholesterolaemia and establishing familial hypercholeserolaemia genetic testing as a clinical diagnostic service
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Health and environmental sciences; Genetic diagnostic service
URI: https://discovery.ucl.ac.uk/id/eprint/10111523
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