APOE gene testing in FH referrals – the story so far

Over 13,000 FH patients from >100 UK referral centres have been tested at Bristol for monogenic and polygenic hypercholesterolaemia using a high throughput NGS panel approach. A monogenic cause was identified in ∼21% of patients, and 80% of monogenic negative patients have a high or intermediate likelihood of a polygenic aetiology. The apolipoprotein E gene (APOE) is a new cause of Autosomal Dominant Familial Hypercholesterolaemia [1]; a common 3bp in-frame deletion, p.(Leu167del), removes a leucine residue in the Low Density Lipoprotein Receptor (LDLR)-binding region of the apo E protein. In vitro cellular studies show a “gain of function” mechanism, whereby very low-density lipoprotein (VLDL) carrying mutant apoE ‘produces LDLR downregulation, thereby raising plasma low-density lipoprotein cholesterol levels’ [2]. APOE has not been widely tested in UK diagnostic laboratories, and as such, there is little data on UK prevalence and penetrance, and the pathogenicity of other variants beyond p.(Leu167del). In a collaborative multicentre pilot study (Bristol, Bath, Gloucester, Wessex, Sheffield, St Georges, West Midlands and Plymouth) 3/317 consented selected patients negative for LDLR, APOB, PCSK9, and LDLRAP1 variants were found to be positive for APOE p.(Leu167del) indicating a prevalence of 0.95%. A further 5 cases, previously tested in Bristol, were detected through the 100,000 genomes project. APOE was incorporated into the Bristol FH v4 assay in Dec 19. Since its introduction, 17/ 4242 FH index patients have tested positive for the APOE p.(Leu167del) variant, indicating a prevalence of 0.4%. To date, APOE p.(Leu167del) cascade testing at Bristol has been undertaken in 29 relatives from 10 families, with 14 further positive cases identified. Examples of non-segregation, in families, indicate that this variant may display non–penetrance, and lifestyle choices may be relevant for disease presentation. A recent report evidences good statin response in APOE p.(Leu167del) patients [3], advocating the benefits of genetic testing. Two FH patients have APOE variants of uncertain significance; c.481A>G p.(Lys161Glu) also located in the LDLR-binding domain and potentially compatible with the proposed gene mechanism, and c.687del p.(Glu230Serfs*21), a likely loss of function variant more compatible with Type III hyperlipoproteinaemia. Our experience of APOE gene testing and recommendations for variant reporting will be presented.

Citation

Duff-Farrier, C., Pennock, M., Watson, E., Forrester, N., Marsh, S., Waite, A., ... & Williams, M. (2021). APOE gene testing in FH referrals–the story so far. Atherosclerosis Plus, 43, S2.

DOI

10.1016/j.athplu.2021.07.003

URI

https://hdl.handle.net/20.500.14709/1068

Usage rights

CC BY-NC-ND 4.0

License

https://creativecommons.org/licenses/by-nc-nd/4.0/