Direct Contact Genetic Screening for High Cholesterol

Overseen By Amber L Beitelshees, PharmD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Maryland, Baltimore

Disqualifiers: None

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the best method for screening family members for high cholesterol risk using direct or indirect contact. It focuses on families with a member carrying a specific genetic change linked to high cholesterol. Participants will either have their family contacted by the study team or will contact them themselves using study-provided materials. The trial seeks individuals carrying the KCNQ1 Met224Thr or APOB Arg3527Gln variant who have first-degree relatives, such as siblings or children, who may also be at risk. As an unphased trial, it offers a unique opportunity to contribute to important genetic research that could benefit families at risk for high cholesterol.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What prior data suggests that this cascade screening method is safe?

Research has shown that directly contacting individuals for genetic screening, as in this study, is generally safe. In similar studies, this method has effectively identified cases of familial hypercholesterolemia, a genetic condition causing high cholesterol, without major safety issues. For example, one study found that directly reaching out to family members successfully identified these cases, with no significant negative effects reported.

Additionally, genetic counseling, which provides guidance for individuals with or at risk for genetic conditions, has been linked to better health outcomes. This suggests that directly contacting family members and offering genetic counseling is well-received.

Overall, there have been no reports of serious unexpected medical problems, indicating that the approach is safe for those involved. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores a new approach to genetic screening for high cholesterol, focusing on direct contact with family members. Unlike traditional methods that rely on individuals to inform their relatives, this approach involves the study team proactively reaching out to family members for cascade screening. This direct method has the potential to identify at-risk individuals more efficiently and ensure they receive timely interventions. By actively involving family members, the trial aims to improve early detection and management of high cholesterol, which could lead to better health outcomes.

What evidence suggests that this method is effective for cascade screening of high cholesterol?

Research has shown that directly contacting family members for genetic screening effectively identifies those at risk for high cholesterol. In this trial, some participants will receive direct contact from the study team for cascade screening of relevant variants. Studies have found that this method helps more family members learn about their risk. Specifically, one study discovered that cascade testing is cost-effective, costing less than $50,000 for each additional year of life gained. This method can identify individuals with familial hypercholesterolemia, a genetic condition that causes high cholesterol, and potentially prevent heart disease. Overall, direct contact screening ensures more people get tested and take steps to manage their cholesterol. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults who carry the KCNQ1 Met224Thr or APOB Arg3527Gln genetic variant, which can be linked to conditions like Long QT Syndrome and high cholesterol. Their first-degree relatives are also eligible as part of a family-based screening approach.

Inclusion Criteria

I carry the KCNQ1 Thr224Met or APOB R3527Q gene mutation.

A close family member has the KCNQ1 Thr224Met or APOB Arg3527Gln mutation.

Exclusion Criteria

N/A

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Randomization and Initial Contact

Participants are randomized into direct or indirect contact arms. Initial contact with family members is made.

2 weeks

1 visit (in-person or virtual)

Cascade Screening

Family members receive pre-test counseling, genetic testing, and post-test counseling.

6 months

In-home visits for genetic testing

Follow-up

Participants are monitored for patient-centered outcomes and implementation evaluation outcomes.

up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Direct contact of family members for cascade screening of relevant variants

Trial Overview The study compares two methods of informing family members about their risk for certain genetic conditions: direct contact by the study team versus indirect contact initiated by the patient (proband). It aims to determine which method is more effective and respectful of privacy.

How Is the Trial Designed?

Group I: Direct contact Experimental Treatment 1 Intervention

Study team contact of family members

Group II: Indirect contact Active Control 1 Intervention

Proband initiated contact of family members

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Published Research Related to This Trial

The clinical trial aims to compare the effectiveness and cost of cascade screening for familial hypercholesterolemia (FH) in patients with and without identifiable pathogenic variants, involving a total of 50 patients each from groups of definite, probable, and possible FH.

By testing family members of patients with definite FH for pathogenic variants and those with probable/possible FH for lipid profiles, the study seeks to identify new cases of FH, which will help refine screening guidelines and improve early detection of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of a Controlled Trial of Cascade Screening for Hypercholesterolemia: The (CASH) Study. Kullo, IJ., Bailey, KR.[2023]

In a study of 183 individuals with familial hypercholesterolemia (FH), key predictors for enrolling relatives in genetic screening included the index-case's LDL-cholesterol levels, their knowledge of family history of dyslipidemia, and the referral source, with those referred through a dedicated website showing higher enrollment rates.

The findings suggest that understanding the clinical and socio-economic characteristics of index-cases can help improve strategies for enrolling at-risk individuals in FH screening programs, potentially enhancing early detection and management of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of Family Enrollment in a Genetic Cascade Screening Program for Familial Hypercholesterolemia. Silva, PRS., Jannes, CE., Oliveira, TGM., et al.[2019]

Familial hypercholesterolemia (FH) is often underdiagnosed, but early detection through cascade screening can significantly reduce health risks for affected individuals and their families.

A study involving 27 index cases (19 from the U.S. and 8 international) found that a majority are open to allowing healthcare providers to directly contact at-risk relatives, suggesting that direct contact could enhance screening efforts for FH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives from individuals with familial hypercholesterolemia on direct contact in cascade screening. Schwiter, R., Brown, E., Murray, B., et al.[2021]

Population-wide genomic screening for familial hypercholesterolemia (FH) can identify individuals at risk for cardiovascular disease, particularly when conducted at younger ages, such as 20 years old, potentially leading to significant health benefits with 111 quality-adjusted life-years (QALYs) gained per 100,000 individuals screened.

Currently, the cost-effectiveness of FH screening is not favorable, with an incremental cost-effectiveness ratio (ICER) of $181,000 per QALY for 20-year-olds; however, reducing the cost of genomic testing to $100 could improve this to $91,000 per QALY, suggesting that lowering costs or integrating FH screening into broader health initiatives could enhance its value.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of population-wide genomic screening for familial hypercholesterolemia in the United States. Spencer, SJ., Jones, LK., Guzauskas, GF., et al.[2023]

Familial hypercholesterolemia (FH) is a common genetic disorder that leads to high LDL cholesterol levels and increased risk of cardiovascular diseases, yet it remains underdiagnosed globally despite available treatments and genetic testing.

This case study highlights the effectiveness of genetic cascade screening in identifying new FH patients, as it successfully identified three relatives of an index patient with a rare LDLR gene variant, demonstrating its potential for preventing cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report. Blokhina, AV., Ershova, AI., Meshkov, AN., et al.[2022]

A nurse-led genetic register successfully identified 121 new cases of heterozygous familial hypercholesterolaemia among 200 first-degree relatives tested, highlighting the effectiveness of targeted screening in detecting this condition early.

The study found that many affected individuals were asymptomatic and had high cholesterol levels, indicating that traditional risk factor screening would have missed most cases, suggesting the need for a more proactive genetic testing approach in lipid clinics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. Bhatnagar, D., Morgan, J., Siddiq, S., et al.[2019]

In a study of 46 individuals (31 probands and 15 additional screened individuals) over 8 years, genetic testing revealed that 71% of unrelated probands had distinct LDLR variants linked to familial hypercholesterolemia (FH), highlighting the importance of genetic testing in diagnosing this condition.

Cascade screening identified adults with less severe FH phenotypes who might not have met previous testing criteria, demonstrating its effectiveness in early detection and management of FH cases that could otherwise remain undiagnosed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Spectrum and Cascade Screening of Familial Hypercholesterolemia in Routine Clinical Setting in Hong Kong. Yip, MK., Kwan, EY., Leung, JY., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8403726/

Cost-effectiveness of cascade genetic testing for familial ... Cascade testing was cost effective, with an average discounted cost per life year gained per person and associated confidence interval of less than $50,000, ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1933287424002228

Implementation outcomes from the IMPACT-FH study Cascade testing can be highly effective in identifying individuals with familial hypercholesterolemia (FH) and help prevent atherosclerotic cardiovascular ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11003060/

Family cascade screening for equitable identification ... This trial will test the comparative effectiveness of these strategies on completion of cascade screening for relatives of individuals with FH, centering ...

4. jacc.org jacc.org/doi/10.1016/j.jacadv.2024.101198

IMPACT-FH Study for Implementing Innovative Family ... The purpose of this study was to evaluate probands' choices of innovative strategies to communicate their FH result with relatives and facilitate cascade ...

5. ahajournals.org ahajournals.org/doi/10.1161/CIRCGEN.119.002723

New Case Detection by Cascade Testing in Familial ... Conclusions: New case detection in familial hypercholesterolemia cascade testing programs tended to be higher with direct contact of relatives, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11606789/

Implementation outcomes from the IMPACT-FH Study - PMC Cholesterol and genetic cascade testing uptake for interview participants were collected by proband report at 6- and 12-month study follow ups.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11355397/

The Impact of Genetic Counseling - PMC - PubMed Central Proband GC was associated with improved medical outcomes and increased FDR cascade testing. Direct contact effectively identified FH cases for ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S1933287423001101

Direct Contact of At-Risk Relatives in the United States ... Genetic Disorders. Direct Contact of At-Risk Relatives in the United States Identifies Familial Hypercholesterolemia Cases.

9. sciencedirect.com sciencedirect.com/science/article/pii/S1098360022007845

A scoping review of interventions increasing screening and ... All studies were effective in increasing FH detection. In total, 12 different intervention types were extracted with the most used being cascade and electronic ...