A comparison of the Netherlands, Norway and UK familial hypercholesterolemia screening programmes with implications for target setting and the UK's NHS long term plan.

We sought to determine the most efficacious and cost-effective strategy to follow when developing a national screening programme by comparing and contrasting the national screening programmes of Norway, the Netherlands and the UK. Comparing the detection rates and screening profiles between the Netherlands, Norway, the UK and constituent nations (England, Northern Ireland, Scotland and Wales) it is clear that maximising the number of relatives screened per index case leads to identification of the greatest proportion of an FH population. The UK has stated targets to detect 25% of the population of England with FH across the 5 years to 2024 with the NHS Long Term Plan. However, this is grossly unrealistic and, based on pre-pandemic rates, will only be reached in the year 2096. We also modelled the efficacy and cost-effectiveness of two screening strategies: 1) Universal screening of 1-2-year-olds, 2) electronic healthcare record screening, in both cases coupled to reverse cascade screening. We found that index case detection from electronic healthcare records was 56% more efficacious than universal screening and, depending on the cascade screening rate of success, 36%-43% more cost-effective per FH case detected. The UK is currently trialling universal screening of 1-2-year-olds to contribute to national FH detection targets. Our modelling suggests that this is not the most efficacious or cost-effective strategy to follow. For countries looking to develop national FH programmes, screening of electronic healthcare records, coupled to successful cascade screening to blood relatives is likely to be a preferable strategy to follow.

Molecular diagnosis of familial hypercholesterolaemia.

PURPOSE OF REVIEW: Familial hypercholesterolaemia is a hereditary disorder of lipoprotein metabolism which causes a lifelong increase in LDL-C levels resulting in premature coronary heart disease. The present review looks at some of the recent literature on how molecular methods can be used to assist in the definitive diagnosis of familial hypercholesterolaemia in a range of patient groups. RECENT FINDINGS: Several recent studies have shown that the prevalence of clinical familial hypercholesterolaemia is higher than previously thought at 1/200 to 1/300, and that 2-5% of patients presenting with early myocardial infarction can be found to have a familial hypercholesterolaemia mutation. The present review then examines different approaches to molecular testing for familial hypercholesterolaemia including point mutation panels versus next-generation sequencing gene panels, and the range of genes tested by some of those panels. Finally, we review the recent evidence for polygenic hypercholesterolaemia within clinically defined familial hypercholesterolaemia patient populations. SUMMARY: To identify patients with familial hypercholesterolaemia within clinically selected patient groups efficiently, a clinical scoring system should be combined with a molecular testing approach for mutations and for polygenic LDL-C single-nucleotide polymorphisms. Alternatively, a population screening methodology may be appropriate, using mutation testing at an early age before significant atherosclerosis has begun. The precise molecular testing method chosen may depend on the clinical presentation of the patient, and/or the population from which they arise.

Genetic diagnosis of familial hypercholesterolaemia using a rapid biochip array assay for 40 common LDLR, APOB and PCSK9 mutations.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) leads to a lifelong increase in plasma LDL levels with subsequent increase in premature vascular disease. Early diagnosis and treatment is the key to effective management of this condition. This research aims to produce a simple and cost effective genetic test which could identify the majority (71%) of mutations causing FH in the UK and Ireland. METHODS: The Randox Biochip Array Technology was used to detect 40 point mutations in LDLR, APOB and PCSK9 genes, over two 5 × 5 arrays. This technology uses multiplex allele specific PCR and biochip array hybridisation, followed by a chemiluminescence detection system and software for automated mutation calling. RESULTS: The FH biochip array assay was validated in the Belfast Genetics Laboratory using 199 cascade screening samples previously sequenced for known FH causing family mutations, the overall sensitivity was 98%. The assay was then used for routine testing of 663 patients with possible FH, from clinics across the UK and Ireland. A total of 49 (7.4%) mutation positive individuals were identified, however, for the clinics in England the detection rate was 12.9%. Further analysis of 120 biochip negative patients, using DNA sequencing, did not identify any false negatives. CONCLUSIONS: The FH biochip array provides a rapid and reliable genetic test for the majority of FH causing point mutations in the UK and Ireland. A total of 32 samples can be run in 3 h. This allows clinics to evaluate additional patients for a possible diagnosis of FH such as patients with high LDL, patients with early onset coronary disease, and patients with relatives known to have FH.

Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate.

Familial hypercholesterolemia (FH) is a common single gene disorder, which predisposes to coronary artery disease. In a previous study, we have shown that in patients with definite FH around 20% had no identifiable gene defect after screening the entire exon coding area of the low density lipoprotein receptor (LDLR) and testing for the common Apolipoprotein B (ApoB) R3500Q mutation. In this study, we have extended the screen to additional families and have included the non-coding intron splice regions of the gene. In families with definite FH (tendon xanthoma present, n=68) the improved genetic screening protocol increased the detection rate of mutations to 87%. This high detection rate greatly enhances the potential value of this test as part of a clinical screening program for FH. In contrast, the use of a limited screen in patients with possible FH (n=130) resulted in a detection rate of 26%, but this is still of significant benefit in diagnosis of this genetic condition. We have also shown that 14% of LDLR defects are due to splice site mutations and that the most frequent splice mutation in our series (c.1845+11 c>g) is expressed at the RNA level. In addition, DNA samples from the patients in whom no LDLR or ApoB gene mutations were found, were sequenced for the NARC-1 gene. No mutations were identified which suggests that the role of NARC-1 in causing FH is minor. In a small proportion of families (<10%) the genetic cause of the high cholesterol remains unknown, and other genes are still to be identified that could cause the clinical phenotype FH.