UCL Genetics Institute


Familial Hypercholesterolemia (FH) Variant Databases


FH is a common (1/500) genetic (autosomal dominant) disorder that results in elevated Low Density Lipoprotein-cholesterol (LDL-C) from birth. The cumulative LDL-C burden causes premature atherosclerosis, so that by the age of 50 years 50% of men and 30% of women have developed evidence of Coronary Heart Disease (CHD). Statin treatment is very effective at lowering LDL-C in FH patients, and in those that are identified before the development of CHD, subsequent life expectancy is no less than in individuals in the general population. Currently, less than 15% of the predicted 120,000 FH patients in the UK have been identified. The 2008 NICE guideline* (CG71) on the identification and management of FH recommend DNA testing be offered to all FH patients to confirm the diagnosis and to assist in the identification of their relatives by systematic “cascade testing”. The FH-causing mutation can currently be found in 70-80% of patients with the strongest clinical suspicion of the disorder, and such DNA-based cascade testing has been very successfully used in a number of countries, particularly Holland, over the last ten years.

DNA causes of FH

Briefly, FH is caused by mutations that directly affect the rate at which LDL-C is cleared from the blood. Mutations in at least three distinct loci cause FH. Mutations in the LDL-Receptor (LDL-R) gene (LDLR) account for the majority of identified mutations, and to date over 1000 are recorded in the UCL database. FH can also be caused by mutations in the gene for apolipoprotein B (APOB), the major protein component of the LDL-cholesterol particle, and the ligand for the removal of the LDL by the LDL-R. One particular mutation (p.R3527Q) in the gene occurs commonly in European subjects, for example in 5-7% of UK patients. The most recently identified gene for FH codes for Protein Convertase Subtilisin/Kexin type 9 (PCSK9), which is an enzyme involved in degrading the LDL-R protein in the lysosome of the cell and preventing it recycling. One common gain of function mutation (p.D374Y) in the PCSK9 gene has been identified which occurs in the UK in ~2% of FH patients.

The FH mutation database

We have established publicly available locus specific databases that list variants identified in the LDLR and PCSK9 genes in FH patients. The information on the database includes predictions of pathogenicity, cross species conservation data and links to the original references where the variants were reported. Researchers have free access to the data listed and may submit variants to the database; these will be curated and made publicly available in due course.


Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE. Ann Hum Genet. 2008 Jul;72(Pt 4):485-98. Epub 2008 Mar 5

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk. Humphries SE, Whittall RA, Hubbart CS, Maplebeck S, Cooper JA, Soutar AK, Naoumova R, Thompson GR, Seed M, Durrington PN, Miller JP, Betteridge DJ, Neil HA; Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee. J Med Genet. 2006 Dec;43(12):943-

Please contact Dr Sarah Leigh (sarah.leigh@ucl.ac.uk) for further information.