Faculty Opinions recommendation of Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.

Abstract Background: Heterozygous Familial Hypercholesterolemia (FH) represents the most frequent monogenic disorder with an estimated prevalence of 1:250 in the general population. Diagnosis during childhood enables early initiation of preventive measures, reducing the risk of severe consecutive atherosclerotic manifestations. Nevertheless, population-based screening programs for FH are scarce.Methods: In the VRONI study children aged 5 to 14 years in Bavaria are invited to participate in a FH screening program during regular pediatric visits. The screening is based on LDL-C measurements from capillary blood. If exceeding 130 mg/dl (3.34 mmol/l), i.e. the expected 95th percentile in this age group, subsequent molecular genetic analysis for FH is performed. Children with FH pathogenic variants enter a registry and are treated by specialized pediatricians. Furthermore, qualified training centers offer FH-focused training courses to affected families. For first degree relatives, reverse cascade screening is recommended to identify and treat affected family members.Results: Implementation of VRONI required intensive prearrangements for addressing ethical, educational, data-safety, legal and organisational aspects, which will be outlined in this paper. Recruitment started in January of 2021, within two months more than 280 pediatricians screened over 1,150 children. Approximately 60,000 children are expected to be enrolled in the VRONI study until 2024. Conclusion: VRONI aims to test the feasibility of a population-based screening for FH in children in Bavaria, intending to set the stage for a nation-wide FH screening infrastructure. Further we aim to validate genetic variants of unclear significance, detect novel causative mutations, and contribute to polygenic risk indices. (German Clinical Trials Register: DRKS00022140; registered August 21st2020.)

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Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia

Genetics in Medicine ◽

10.1038/s41436-018-0311-2 ◽

2018 ◽

Vol 21 (5) ◽

pp. 1173-1180 ◽

Cited By ~ 11

Author(s):

Maris Alver ◽

Marili Palover ◽

Aet Saar ◽

Kristi Läll ◽

Seyedeh Maryam Zekavat ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Population Based ◽

Cascade Screening

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Improving Familial Hypercholesterolemia Index Case Detection: Sequential Active Screening from Centralized Analytical Data

Journal of Clinical Medicine ◽

10.3390/jcm10040749 ◽

2021 ◽

Vol 10 (4) ◽

pp. 749

Author(s):

Fernando Sabatel-Pérez ◽

Joaquín Sánchez-Prieto ◽

Víctor Manuel Becerra-Muñoz ◽

Juan Horacio Alonso-Briales ◽

Pedro Mata ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Diagnostic Yield ◽

Low Density Lipoprotein ◽

Analytical Data ◽

Genetic Diagnosis ◽

Density Lipoprotein ◽

Screening Strategy ◽

Cascade Screening ◽

Active Screening ◽

Lipid Clinic

The majority of familial hypercholesterolemia index cases (FH-IC) remain underdiagnosed and undertreated because there are no well-defined strategies for the universal detection of FH. The aim of this study was to evaluate the diagnostic yield of an active screening for FH-IC based on centralized analytical data. From 2016 to 2019, a clinical screening of FH was performed on 469 subjects with severe hypercholesterolemia (low-density lipoprotein cholesterol ≥220 mg/dL), applying the Dutch Lipid Clinic Network (DLCN) criteria. All patients with a DLCN ≥ 6 were genetically tested, as were 10 patients with a DLCN of 3–5 points to compare the diagnostic yield between the two groups. FH was genetically confirmed in 57 of the 84 patients with DLCN ≥ 6, with a genetic diagnosis rate of 67.9% and an overall prevalence of 12.2% (95% confidence interval: 9.3% to 15.5%). Before inclusion in the study, only 36.8% (n = 21) of the patients with the FH mutation had been clinically diagnosed with FH; after genetic screening, FH detection increased 2.3-fold (p < 0.001). The sequential, active screening strategy for FH-IC increases the diagnostic yield for FH with a rational use of the available resources, which may facilitate the implementation of FH universal and family-based cascade screening strategies.

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Detection of Familial Hypercholesterolemia Using Next Generation Sequencing in Two Population-Based Cohorts

Chonnam Medical Journal ◽

10.4068/cmj.2018.54.1.31 ◽

2018 ◽

Vol 54 (1) ◽

pp. 31 ◽

Cited By ~ 3

Author(s):

Hee Nam Kim ◽

Sun-Seog Kweon ◽

Min-Ho Shin

Keyword(s):

Next Generation Sequencing ◽

Familial Hypercholesterolemia ◽

Population Based ◽

Next Generation ◽

Generation Sequencing

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Abstract 12169: LDL-C Levels and Treatment Patterns Among Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry

Circulation ◽

10.1161/circ.132.suppl_3.12169 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Emil M deGoma ◽

Zahid S Ahmad ◽

Emily O'Brien ◽

Iris Kindt ◽

Peter Shrader ◽

...

Keyword(s):

Statin Therapy ◽

Familial Hypercholesterolemia ◽

High Intensity ◽

The United States ◽

Treatment Patterns ◽

Atherosclerotic Cardiovascular Disease ◽

Cascade Screening ◽

Cross Sectional ◽

Lowering Therapy ◽

Care Gaps

Introduction: In the US, LDL-C levels and treatment patterns of patients with familial hypercholesterolemia (FH) – a group prioritized for statin therapy in the 2013 ACC/AHA cholesterol guidelines – remain poorly described. In 2013 the FH Foundation launched the CAscade SCreening for Awareness and DEtection (CASCADE) of FH Registry, the only active US FH patient registry addressing this knowledge gap. Methods: We conducted a 2-year (2013-2015) cross-sectional analysis among 1,295 adults with heterozygous FH enrolled in the CASCADE FH Registry from 10 US lipid clinics. Results: Mean (SD) age at enrollment was 54 (16) years; mean age at FH diagnosis was 45 (19) years; 59% were female; and 80% were white. Mean pretreatment and post-treatment LDL-C levels were 256 (66) and 156 (71) mg/dl, respectively. At enrollment, 43% of patients were taking high-intensity statin therapy; 25% were not taking a statin; and 45% received >1 LDL-lowering therapy. Among FH patients on LDL-lowering therapy, 25% achieved an LDL-C <100 mg/dl, and 41% achieved a ≥50% LDL-C reduction (Table). Factors associated with a ≥50% LDL-C reduction included high-intensity statin use (adjusted OR 2.24, 95% CI 1.47-3.42) and use of >1 LDL-lowering therapy (1.94, 1.29-2.93) (Figure). Atherosclerotic cardiovascular disease (ASCVD) was present in 37%, of whom 44% achieved a ≥50% LDL-C reduction and 9% achieved an LDL-C <70 mg/dl. Conclusions: Despite the high prevalence of ASCVD, several care gaps exist for FH patients enrolled in the CASCADE US registry: lack of early diagnosis, insufficient use of high-intensity statin therapy, and failure to achieve adequate LDL-C reductions.

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Genetics of Hypercholesterolemia: Comparison Between Familial Hypercholesterolemia and Hypercholesterolemia Nonrelated to LDL Receptor

Frontiers in Genetics ◽

10.3389/fgene.2020.554931 ◽

2020 ◽

Vol 11 ◽

Author(s):

Estíbaliz Jarauta ◽

Ana Ma Bea-Sanz ◽

Victoria Marco-Benedi ◽

Itziar Lamiquiz-Moneo

Keyword(s):

Cardiovascular Risk ◽

Familial Hypercholesterolemia ◽

Genetic Defect ◽

Genetic Diagnosis ◽

Ldl Receptor ◽

Lipid Lowering ◽

Atherosclerotic Cardiovascular Disease ◽

Single Nucleotide Variants ◽

Cascade Screening ◽

The Moment

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) >95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene (LDLR, APOB, PCSK9, or ApoE), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Nevertheless, an important proportion of serious HC cases, denominated polygenic hypercholesterolemia (PH), may be attributed to the small additive effect of a number of single nucleotide variants (SNVs), located along the whole genome. The diagnosis, prevalence, and cardiovascular risk associated with PH has not been fully established at the moment. Cascade screening to detect a specific genetic defect is advised in all first- and second-degree relatives of subjects with FH. Conversely, in the rest of cases of HC, it is only advised to screen high values of LDL-C in first-degree relatives since there is not a consensus for the genetic diagnosis of PH. FH is associated with the highest cardiovascular risk, followed by PH and other forms of HC. Early detection and initiation of high-intensity lipid-lowering treatment is proposed in all subjects with severe HC for the primary prevention of ASCVD, with an objective of LDL-C <100 mg/dl or a decrease of at least 50%. A more aggressive reduction in LDL-C is necessary in HC subjects who associate personal history of ASCVD or other cardiovascular risk factors.

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Risk Communication in Families of Children with Familial Hypercholesterolemia: Identifying Motivators and Barriers to Cascade Screening to Improve Diagnosis at a Single Medical Center

Journal of Genetic Counseling ◽

10.1007/s10897-018-0290-0 ◽

2018 ◽

Vol 28 (1) ◽

pp. 50-58 ◽

Cited By ~ 5

Author(s):

Elisabeth Wurtmann ◽

Julia Steinberger ◽

Pat McCarthy Veach ◽

Mindi Khan ◽

Heather Zierhut

Keyword(s):

Risk Communication ◽

Familial Hypercholesterolemia ◽

Medical Center ◽

Cascade Screening

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Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: many happy returns on investment?

European Heart Journal ◽

10.1093/ehjci/ehaa946.3535 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

Z Ademi ◽

R Norman ◽

J Pang ◽

D Liew ◽

S Zoungas ◽

...

Keyword(s):

Cost Effectiveness ◽

Usual Care ◽

Familial Hypercholesterolemia ◽

Health Economic Evaluation ◽

Mendelian Randomisation ◽

Public Healthcare ◽

Cascade Screening ◽

Care Cascade ◽

Life Years ◽

The Cost

Abstract Background There are no studies that have specifically investigated the cost-effectiveness of cascade screening of children for heterozygous familial hypercholesterolemia (FH) and treatment of affected individuals with statins to prevent coronary heart disease (CHD). Purpose This study explores the cost-effectiveness of this strategy from the perspective of the Australian public healthcare system. Methods A lifetime Markov model with four health states (Alive without CHD, Alive with CHD, Dead from fatal CHD, and Dead from other causes) was developed to simulate the progression of ten- year-old children screened for FH and treated immediately with statins if found to have FH. The underlying prevalence of FH in this target population was assumed to be 56.8%, and the sensitivity and specificity of testing was 100%. The comparator was usual care, which assumed that subjects started statins spontaneously at a later point or when they experienced a cardiovascular event. The effect of reducing low-density lipoprotein cholesterol (LDL-C) on the risk of a first event at each age assumed that risk was proportional to total lifetime exposure and was implemented using Mendelian randomisation analysis data. Cost and other outcome data were sourced from published sources. Outcome of interests were costs in Australian dollars (AUD), life years gained (LYG) and quality-adjusted life years (QALYs) gained, as well as incremental cost-effectiveness ratios (ICERs) of costs per LYG and per QALY gained. All future costs and outcomes were discounted by 5% annually. Results Undiscounted results showed that compared with usual care, cascade screening of ten year-old children for FH and initiation of treatment of affected individuals saved 7.77 LYG and 7.53 QALYs per person over a lifetime. With 5% annual discounting, there were 0.97 LYG and 1.07 QALYs gained per person, at an additional cost of $3,244. These equated to ICERs of $3334 per LYG and $3023 per QALY gained. The equivalent ICERs in USD would be $5089 per LYG gained and $4615 per QALY gained. Sensitivity analysis showed the results to be robust. Conclusions Compared to usual care, cascade screening of ten year old children for FH and treating affected individuals is likely to be highly cost-effective. Table 1. Granular cost and benefit data Funding Acknowledgement Type of funding source: None

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Prognostic impact of cascade screening for familial hypercholesterolemia on cardiovascular events

European Heart Journal ◽

10.1093/ehjci/ehaa946.2983 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Tada ◽

H Okada ◽

A Nomura ◽

A Nohara ◽

M Yamagishi ◽

...

Keyword(s):

Risk Factors ◽

Familial Hypercholesterolemia ◽

Cardiovascular Events ◽

Lipid Lowering ◽

Funding Source ◽

Atherosclerotic Cardiovascular Disease ◽

Prognostic Impact ◽

Cascade Screening ◽

Ascvd Risk ◽

The Impact

Abstract Background Early diagnosis and timely treatment for the patients with familial hypercholesterolemia (FH) can substantially lower the risk of atherosclerotic cardiovascular disease (ASCVD). In this sense, cascade screening could be one of the most useful options. However, few data exist regarding the impact of cascade screening for FH on the reduction of risk of ASCVD events. Objectives We aimed to evaluate the prognostic impact of cascade screening for FH. Methods We retrospectively investigated the health records of 1,050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiovascular events (MACE). The median period of follow-up was 12.3 years (interquartile range [IQR] = 9.1–17.5 years), and MACE included death from any causes or hospitalization due to ASCVD events. Results During the observation period, 246 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P<0.001), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.36; 95% CI = 0.22 to 0.60; P<0.001) when compared with the probands, even after adjusting for those known risk factors. Conclusions The identification of patients with FH via cascade screening appeared to result in better prognoses. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Scientific research grants from the Ministry of Education, Science and Culture of Japan (no. 16K19394, 18K08064, and 19K08575)

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