DNA Testing in Familial Hypercholesterolaemia (FH) patients
The usefulness of a molecular DNA test to provide an unequivocal diagnosis for a patient with a clinical diagnosis of FH is becoming increasingly realised. FH is caused by mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB) or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (8).
As shown in the pie chart above, the most common class of genetic defect is a mutation in the LDLR gene. We have recently updated the UCL FH database, and currently over 1200 mutations have been reported world-wide, with >300 different mutations being reported in UK patients. Even when exhaustively screened, in a small proportion of those with a diagnosis of Definite FH subjects (10-15%) and a larger proportion of Possible FH patients (60-75%) no mutation can be found. This may be because of failure to detect all DNA changes present using current methods, because the mutation is in a part of the genes not currently covered (eg introns), because the mutation is in a yet-to-be identified gene, or (most likely) because of the inclusion of non-FH patients (ie a clinical false positive diagnosis).
Cascade testing is a cost-effective method of finding additional FH patients (7), and has been used extensively in other countries in Europe, most notably in Holland for the last five years. Identified FH patients are then helped to make changes in lifestyle including dietary intervention, and all require drug treatment. The British Heart Foundation has recently announced pump-priming funding for 29 “FH Nurses” in 14 centres UK-wide, to help identify more FH patients and carry out cascade testing in families with an identified mutation, and this will be of enormous benefit to the patients and their relatives.
Current NICE guidelines (CG71, 2008) for the management of FH are that cascade testing of at least first and second degree relatives of FH probands should be carried out, based on a mutation where it can be identified and based on LDL-C measures where no mutation can be identified. We now believe that in the vast majority of the no-mutation patients the cause of their hypercholesterolemia is “polygenic” and not due to a single unknown gene (15). While such patients require management of their plasma lipid levels, cascade testing in their relatives is clinically of less use than in the monogenic families where 50% of their first degree relatives are “at-risk” of FH.