Background: Familial Hypercholesterolaemia (FH) is a monogenic disorder of Low Density Lipoprotein (LDL) metabolism which can be specifically diagnosed by genetic testing. However LDL-cholesterol (LDL-C) estimation has the drawback that it requires a fasting sample, because the Friedewald formula uses a factor relating to fasting triglyceride. Also other cholesterol containing lipoproteins are atherogenic and should be considered as part of cardiovascular risk assessment. Recent guidelines from National Institute for Health and Care Excellence (NICE) recommend non-HDL cholesterol (non HDL-C) for assessment of cardiovascular risk. The Joint British Societies (JBS3) guideline also recommends non-HDL cholesterol and proposes a conversion factor: Non-HDL-C = 1.24 × LDL-C. This project assessed the application of this factor in patients who have presented to lipid clinics as possible FH.

s / Atherosclerosis 245 (2016) e243ee251 e247 the degree of atherosclerosis in monogenic FH patients versus polygenic individuals with hypercholesterolaemia. Method: Carotid Intima Media Thickness (cIMT) was measured by B-mode ultrasound in three different segments of carotid arteries (common carotid artery, bulb and internal carotid artery) in 86 individuals (53 female and 33 male) with a clinical diagnosis of FH (LDL-Cmean+SD: 5.8 ± 1.3mmol/l). 56 patients had monogenic FH with a known mutation in the LDLR or APOB gene and 30 patients had no mutation but they had a score in the top two quartiles of a six LDL-C-raising SNPs gene score. Results: The monogenic patients were younger than polygenic individuals (50 ± 14 years vs 57 ± 12 years, p 1⁄4 0.03). There was no significant difference in total cholesterol level, LDL-C and HDL-C between the two groups. Triglyceride level was significantly higher in polygenic compared to monogenic group [1.6 ± 0.7 mmol/l vs 1.2 ± 0.5 mmol/l, p 1⁄4 0.01]. After adjustment for age and gender, the mean of all the cIMT measurements was significantly higher in monogenic than polygenic patients [0.74 mm (0.7e0.79) vs 0.66 mm (0.61e0.72), p 1⁄4 0.03]. Conclusion: The severity of atherosclerosis as measured by cIMT is higher in monogenic FH individuals than the polygenic group. While LDL-C levels need to be reduced in both groups, the greater degree of carotid atherosclerosis supports aggressive management of their LDL-C levels with potent statins and other LDL-C lowering modalities in combination. Referred to specialist care 48 (77%) GP managing patient 3 (5%)

Selection of patients who are appropriate for genetic testing for FH is a balance between diagnostic yield and cost. The Wales FH service has implemented a clinical scoring system to guide the selection of patients based on lipid levels, personal and family history of cardiovascular disease plus physical signs. In an evaluation of 623 patients referred to lipid clinics, the proportion of patients with a mutation ranged from 4% in those scoring 5 or less to 85% in those scoring >15.

Genetic testing of 1570 hypercholesterolaemic index patients from lipid clinics in the Wales FH service found a pathogenic mutation in 22% and a genetic variant of uncertain significance (VUS) in 9% (136 individuals, 89 variants). The designation of a variant as VUS precludes its use for diagnostic cascade testing and causes uncertainty for patients and clinicians.

Raised cholesterol is common in healthcare settings, with over 8 million patients currently being treated with lipid lowering medications in the United Kingdom alone. It is important that individuals with Familial Hypercholesterolaemia (FH) are specifically identified, because of the importance of diagnosing younger family members by cascade testing.

BACKGROUND/OBJECTIVE:Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner.METHODS:623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria.RESULTS:The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score.CONCLUSION:These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH.

Genetic testing of 1191 index patients from lipid clinics in the Wales FH service revealed a pathogenic mutation in 23% and a genetic variant of uncertain significance (VUS) in 8% (102 individuals, 67 variants). A VUS is a DNA sequence variant for which there is insufficient laboratory or clinical evidence to designate the variant as causative or not. Finding a VUS leaves the diagnosis uncertain for patients and cannot be used for family cascade testing. In this study family members are tested for LDL-cholesterol and VUS with the aim of assessing whether the variant tracks with LDL-C. Specialist genetic association statistical analysis can be used to quantify the likelihood of pathogenicity based on the family relationship, number of subjects, and LDL-C (with adjustment for age and gender), allowing for the genetic relatedness between family members. Data from families who share the same VUS can be combined. Data from 51 family members with 11 different variants has been collected to date, concentrating first on those with more extensive families available for testing. All available members have been tested in three families, with each family having a different VUS in the LDLR gene. Analysis showed the VUS to be significantly associated with LDL-C in two families (c.2087G>A p=0.007) (c.1073G>A; p=0.002), but not in the other (c.2098G>A; p=0.14) indicating that in two families the variant is likely to be pathogenic whereas in the third it is not. This study demonstrates the feasibility and value of a quantitative statistical approach to family studies compared to qualitative segregation studies which do not take into account the concentration of LDL-C. This approach provides useful additional evidence for the genetic diagnostic laboratory which can be shared with other centres using anonymous genetic data bases for FH. The information helps clinicians provide more clarity for their patients and families.

The Wales FH service, launched in Sept 2010 has been developed based on NICE guidance to provide a coordinated approach to cascade testing for FH and other aspects of diagnosis and clinical management. Prior to this there was no cascade testing offered and inequitable service provision.

Background: People with familial hypercholesterolaemia (FH) face lifelong medication and lifestyle choices. An accurate understanding of the comparative benefits from different preventive strategies can help them make rational decisions based on individual circumstances.

A clinical scoring system has been developed for the Wales FH service as a guide for clinicians to determine whether lipid clinic patients with a clinical diagnosis of possible FH are suitable for FH genetic testing. This is based on a modification of the Dutch Lipid Clinic Network scoring criteria.

Aneurin Bevan Health Board (ABHB) has an approx population of 561,000. At the time of the launch of the all Wales FH testing service, December 2010, there were three lipid clinic sessions a month, seeing on average 12 new patients per month. New patient waiting lists were in excessive of 6months, managed only by initiative clinics, twice a month.

The Wales FH cascade service was launched in December 2010 with the introduction of a diagnostic service for FH, combined with family cascade testing. An FH genotyping scoring system was developed to guide whether lipid clinic patients with a clinical diagnosis of FH are suitable for FH genetic testing. This was based on a modification of the Dutch Lipid Clinic Network scoring criteria.