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Genetic testing for Familial Hypercholesterolaemia - Past, Present and Future

Futema, M; Taylor-Beadling, A; Williams, M; Humphries, SE; (2021) Genetic testing for Familial Hypercholesterolaemia - Past, Present and Future. Journal of Lipid Research , Article 100139. 10.1016/j.jlr.2021.100139. (In press). Green open access

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In the early 1980s, the Nobel Prize winning cellular and molecular work of Mike Brown and Joe Goldstein led to the identification of the Low Density Lipoprotein Receptor (LDLR) gene as the first gene where mutations cause the Familial Hypercholesterolaemia (FH) phenotype. We now know that autosomal dominant monogenic FH can be caused by pathogenic variants of three additional genes (APOB/PCSK9/APOE), and that the plasma LDL-C concentration and risk of premature Coronary Heart Disease (CHD) differs according to the specific locus and associated molecular cause. It is now possible to use Next Generation Sequencing (NGS) to sequence all exons of all four genes, processing 96 patient samples in one sequencing run, increasing the speed of test results and reducing costs. This has resulted in the identification of many novel FH-causing variants, but also some "Variants of Unknown Significance (VUSs)" which require further evidence to classify as pathogenic or benign. The identification of the FH-causing variant in an index case can be used as an unambiguous and rapid test for other family members. An FH-causing variant can be found in 20%-40% of patients with the FH phenotype, and we now appreciate that in the majority of patients without a monogenic cause, a polygenic aetiology for their phenotype is highly likely. Compared to those with a monogenic cause, these patients have significantly lower risk of future CHD. The use of these molecular genetic diagnostic methods in the characterization of FH is a prime example of the utility of precision or personalised medicine.

Type: Article
Title: Genetic testing for Familial Hypercholesterolaemia - Past, Present and Future
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jlr.2021.100139
Publisher version: https://doi.org/10.1016/j.jlr.2021.100139
Language: English
Additional information: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
Keywords: LDL-C, LDLR, Monogenic, SNP-Score, Variants of Unknown Significance (VUS), clinical utility, coronary heart disease, index case, next-generation sequencing, polygenic
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
URI: https://discovery.ucl.ac.uk/id/eprint/10136921
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