Cascade screening program for familial hypercholesterolemia

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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Abstract 15779: Quality of Life in a Cohort of Familial Hypercholesterolemia Patients Undergoing Molecular Cascade Screening in Brazil

Circulation ◽

10.1161/circ.132.suppl_3.15779 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Ana Cristina Souto ◽

Alexandre Pereira ◽

Cinthia E Jannes ◽

Julia Fukushima ◽

Jose E Krieger ◽

...

Keyword(s):

Quality Of Life ◽

Familial Hypercholesterolemia ◽

Linear Models ◽

Screening Program ◽

Short Form ◽

Smoking Habit ◽

Genetic Diagnosis ◽

Cascade Screening ◽

Social Demographic

Introduction:: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated disease associated with elevated risk of early cardiovascular disease (CVD) and thus can reduce quality of life. The present health related quality of life (HRQL) investigation, evaluated patients personal interpretation of morbidity burden in daily life. Methods: The study included a total of 1,032 adult individuals participating in a FH molecular cascade-screening program. The involved individuals were index cases (IC n=363), with genetic diagnosis or FH and their first-degree relatives (FDR, n=669). All patients were evaluated at the first session of the molecular diagnosis process. HRQL measurements, mental (MCS) and physical (PCS) component scores, was carried out with the Medical Outcomes Study (MOS) 12-Item Short-Form Health Survey (SF-12) questionnaire. Results: IC were older (52±13.1 vs. 46±16.2 years, P<0.05) and presented lower PCS than FDR (44.7±9.3 vs. 49.2±8.4, P<0.05). No differences were seen on the MCS component. Overall, generalized linear models showed that smoking habit (11.9% prevalence, P=0.006), previous diagnosis of hyperlipidemia (78.6%, P=0.020) and depression (13.5% prevalence, P<0.000) were significant predictors of MCS. The presence of heart failure (6.5%, P=0.018), angina pectoris (12.9%, P=0.005), previous myocardial infarction (12.3%, P=0.012), hypertension (33.9%, P=0.018) and obesity (12.8%, P<0.000) were all predictors of PCS. The presence of arrhythmias (10.7% prevalence) predicted both MCS and PCS (P=0.042 and P=0.00, respectively). Male gender (42.4%, P<0.000) and education level (< 9 years of background, 28% P<0.000) were social-demographic aspects predictive of differences in MCS and PCS, respectively. Conclusions: Reductions in the individuals’ reported quality of life were explained by differences in social-demographic characteristics but mainly by inadequate health/disease status, such as risk factors and previous CVD. Active FH genetic cascade diagnosis by promoting early and adequate medical care and thus preventing early CVD, may improve substantially the subjective appraisal of HRQL.

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Communicating Risk With Relatives in a Familial Hypercholesterolemia Cascade Screening Program

The Journal of Cardiovascular Nursing ◽

10.1097/jcn.0000000000000153 ◽

2015 ◽

Vol 30 (4) ◽

pp. E1-E12 ◽

Cited By ~ 8

Author(s):

Melanie Allison

Keyword(s):

Familial Hypercholesterolemia ◽

Screening Program ◽

Cascade Screening ◽

Communicating Risk

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Abstract 15576: Cardiovascular Disease in Elderly Familial Hypercholesterolemia Individuals Attending a Cascade Screening Program

Circulation ◽

10.1161/circ.142.suppl_3.15576 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

elaine coutinho ◽

Marcio H Miname ◽

Viviane Z Rocha ◽

Marcio S Bittencourt ◽

Cinthia Jannes ◽

...

Keyword(s):

Cardiovascular Disease ◽

Familial Hypercholesterolemia ◽

High Intensity ◽

Screening Program ◽

Coronary Revascularization ◽

Genetic Diagnosis ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Cvd Risk ◽

Cascade Screening

Introduction: Familial hypercholesterolemia (FH) is associated with early onset of cardiovascular disease (CVD) and mortality. Lipid lowering treatment (LLT) may change the natural history of FH, however there is scant information about elderly individuals (older than 60 years) with FH. This study describes characteristics of elderly FH individuals presenting or not CVD. Hypothesis: Monogenic defects are important markers of CVD risk and initiation and long-term use of lipid lowering therapy (LLT) is relevant to minimize this risk. Methods: Cross-sectional analysis of clinical and laboratory of molecularly proven elderly FH (FH+) and non-affected (FH-) individuals attending a cascade screening program. FH+ were divided in those presenting or not CVD (defined as previous myocardial infarction or ischemic stroke, carotid or coronary revascularization and angina with stenosis ≥50% on angiography). Results: From 4,111 genotyped individuals, 462 (11.2%) elders were included (198 FH+ and 264 FH-). There was predominance of females in either groups, however with more men in FH+ 37.4% vs. 24.2%, p=0.002. No differences were seen between FH+ and FH- regarding age, [median (%25;75%)] 66 (62;71) and 66 (63;71) years, p=0.68; use of LLT 88.5% vs. 91.5%, p=0.29 and high intensity LLT 61.7 % vs. 55.8%, p=0.20, respectively. Despite longer LLT duration in FH+ 11(7;20) vs. 7 (3;13) years, p<0.001, in either groups LLT was started late, at 54 (47;61) and 59 (52;64) years, p <0.001, respectively in FH+ and FH-. FH+ had higher LDL-C at diagnosis, 243 (179;302) vs. 228 (209;251) mg/dL, p=0.013, as well as greater frequencies of previous CVD 40.9% vs. 27.3%, p=0.002, and early CVD 22.2% vs. 9.0%, p<0.001. In FH+, male sex [OR (95%CI)] 5.29 (2.25-12.45), p<0.001, and use of high intensity LLT 2.51 (1.08-5.87), p=0.03, were independently associated with CVD. Conclusions: The genetic diagnosis of FH was associated with higher rates of CVD and early CVD vs. FH- hypercholesterolemics. Elders with FH+ who survived despite late LLT initiation have a worse CVD history than FH- elders, emphasizing the relevance of a monogenic defect as cause of long-lasting hypercholesterolemia and CVD risk, particularly in men.

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Stakeholder Views on Active Cascade Screening for Familial Hypercholesterolemia

Healthcare ◽

10.3390/healthcare6030108 ◽

2018 ◽

Vol 6 (3) ◽

pp. 108 ◽

Cited By ~ 4

Author(s):

Carla van El ◽

Valentina Baccolini ◽

Peter Piko ◽

Martina Cornel

Keyword(s):

The Netherlands ◽

Familial Hypercholesterolemia ◽

Screening Program ◽

Family Members ◽

Preventive Strategy ◽

Cascade Screening ◽

Privacy Regulation ◽

Psychological Burden ◽

Roles And Responsibilities ◽

Screening Programs

In familial hypercholesterolemia (FH), carriers profit from presymptomatic diagnosis and early treatment. Due to the autosomal dominant pattern of inheritance, first degree relatives of patients are at 50% risk. A program to identify healthy relatives at risk of premature cardiovascular problems, funded by the Netherlands government until 2014, raised questions on privacy and autonomy in view of the chosen active approach of family members. Several countries are building cascade screening programs inspired by Dutch experience, but meanwhile, the Netherlands’ screening program itself is in transition. Insight in stakeholders’ views on approaching family members is lacking. Literature and policy documents were studied, and stakeholders were interviewed on pros and cons of actively approaching healthy relatives. Sociotechnical analysis explored new roles and responsibilities, with uptake, privacy, autonomy, psychological burden, resources, and awareness as relevant themes. Stakeholders agree on the importance of early diagnosis and informing the family. Dutch healthcare typically focuses on cure, rather than prevention. Barriers to cascade screening are paying an own financial contribution, limited resources for informing relatives, and privacy regulation. To benefit from predictive, personalized, and preventive medicine, the roles and responsibilities of stakeholders in genetic testing as a preventive strategy, and informing family members, need to be carefully realigned.

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Familial hypercholesterolemia in Brazil: Cascade screening program, clinical and genetic aspects

Atherosclerosis ◽

10.1016/j.atherosclerosis.2014.11.009 ◽

2015 ◽

Vol 238 (1) ◽

pp. 101-107 ◽

Cited By ~ 46

Author(s):

Cinthia E. Jannes ◽

Raul D. Santos ◽

Pãmela R. de Souza Silva ◽

Luciana Turolla ◽

Ana C.M. Gagliardi ◽

...

Keyword(s):

Familial Hypercholesterolemia ◽

Screening Program ◽

Cascade Screening

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Quality Assessment of the Genetic Test for Familial Hypercholesterolemia in The Netherlands

Cholesterol ◽

10.1155/2013/531658 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Iris Kindt ◽

Roeland Huijgen ◽

Marieke Boekel ◽

Kristiaan J. van der Gaag ◽

Joep C. Defesche ◽

...

Keyword(s):

The Netherlands ◽

Familial Hypercholesterolemia ◽

Screening Program ◽

Reference Laboratory ◽

Test Results ◽

Cascade Screening ◽

Dna Test ◽

Increased Risk ◽

A Prospective Study ◽

Positive Results

Introduction. Familial hypercholesterolemia (FH) is an inherited disorder associated with a severely increased risk of cardiovascular disease. Although DNA test results in FH are associated with important medical and ethical consequences, data on accuracy of genetic tests is scarce. Methods. Therefore, we performed a prospective study to assess the overall accuracy of the DNA test used in the genetic cascade screening program for FH in The Netherlands. Individuals aged 18 years and older tested for one of the 5 most prevalent FH mutations, were included consecutively. DNA samples were analyzed by the reference and a counter-expertise laboratory following a standardized procedure. Results. 1003 cases were included. In the end, 317 (32%) carried an FH mutation, whereas in 686 (69%) samples no mutation was found. The overall accuracy of the reference laboratory was 99.8%, with two false positive results identified by the counter-expertise laboratory. Conclusion. The currently used mutation analysis is associated with a very low error rate. Therefore, we do not recommend routine use of duplicate testing.

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Cascade screening and treatment of children with familial hypercholesterolemia in Turkey

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0234 ◽

2020 ◽

Vol 33 (10) ◽

pp. 1251-1256

Author(s):

Engin Kose ◽

Melis Kose ◽

Sureyya Ipek Ozturk ◽

Esra Ozcan ◽

Huseyin Onay ◽

...

Keyword(s):

Coronary Artery ◽

Familial Hypercholesterolemia ◽

Cause Of Death ◽

Screening Program ◽

Developed Countries ◽

Statin Treatment ◽

Lipid Lowering ◽

Cascade Screening ◽

Lipid Screening ◽

The Mean

AbstractObjectivesPremature coronary artery disease is the most common preventable cause of death in developed countries, and familial hypercholesterolemia (FH) is the most common monogenetic disorder of lipid metabolism, predisposing for premature coronary artery. FH is the most common preventable cause of death in developed countries. In 2016, the national lipid screening program in school-age children has been started in Turkey. In this study, we aimed to evaluate the efficacy of lipid screening program, lipid-lowering treatments, and the challenges of treatments in children diagnosed with FH.MethodsPatients diagnosed with FH in the pediatric metabolism outpatient clinic were retrospectively evaluated. Changes in lipid profile with dietary interventions and statin treatments were assessed. The results of cascade screening were analyzed.ResultsFifty-one patients diagnosed with FH were enrolled in the study. Twenty-four (47.1%) were female. The mean age of the patients was 9.8 ± 3.2 years. Heterozygous LDLR gene mutation was detected in all patients. Three novel pathogenic variations were revealed with the genetic investigation. Forty-one (80.4%) patients had high adherence to CHILD-2 dietary recommendations. The mean low-density lipoprotein cholesterol (LDL-C) level decreased by 14.5 ± 7.6% after dietary intervention. Parents refused to start statin treatment in 8 (15.7%) patients. Statin treatment was initiated to 22 (43.1%) patients. Mean LDL-C level decreased from 204.1 ± 19.1 mg/dL to 137.0 ± 13.1 mg/dL. In cascade screening, 7 (13.7%) parents without a diagnosis of FH were diagnosed with FH. After the screening program, statin treatment was initiated for 18 (35.3%) parents and 7 (16.3%) siblings.ConclusionsWe can conclude that screening for FH in children is crucial for diagnosing FH not only in children but also in their relatives. Although statins are safe and effective in achieving the target LDL-C level, we determined significant resistance for initiating statin treatment in patients.

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