The Dutch cascade screening model for FH was the most successful of such programs in the world. It remains unclear whether aspects of the Dutch model (i.e. direct engagement with FH probands and relatives outside usual healthcare settings) are feasible in the US. This is especially important since prior attempts at cascade screening in the US have had very low screening rates (<10% of families screened).
We conducted a multi-site single-arm proof-of-concept study in which the US-based FH Foundation (a 501c3 research and advocacy organization) directly engaged with FH probands and relatives similar to the approach taken by the Dutch “Foundation for Tracing FH.”
Eleven unrelated probands with genetically confirmed FH were enrolled. Mean age was 43 years; 82% were women, and 82% were of European ancestry. Prior to enrolling into the study, only 2 families (18% screening rate) were screened for FH with both lipid measurements and genetic testing. Two probands declined cascade screening due to fear over genetic discrimination. Nine total relatives engaged with the FH Foundation. Mean age was 43 years and 44% were women. Seven of those relatives (from 6 families; 55% screening rate) consented to be screened for FH with lipid measurement and genetic testing. The two additional relatives – men ages 39 and 49 – agreed to lipid measurements but not genetic testing, each noting he would like to think more about genetic testing.
Our proof-of-concept study demonstrates the feasibility of the FH Foundation engaging FH probands and their relatives outside the usual healthcare settings for cascade screening, similar to the Dutch model. We found only 18% of families had already been screened, and after engaging with the FH Foundation, 55% of families were willing to participate in cascade screening. These findings suggest the methods described here may improve cascade screening rates in the US.
Familial Hypercholesterolemia (FH) is a common genetic disorder (estimated prevalence: 1 in 250 individuals) characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) from birth onward , resulting in significantly increased risk for early atherosclerotic cardiovascular disease (ASCVD). One in 10 premature myocardial infarctions (MIs) is caused by FH. Yet 90% of the 1.3 million United States (US) residents living with FH remain undiagnosed , suggesting a missed opportunity for ASCVD prevention.
As an autosomal dominant genetic disorder, first degree relatives of a person with FH have a 50% chance of also having FH . Cascade screening – the process of screening relatives of an proband (i.e. index case) for FH – has the potential to identify up to 8 additional FH cases per proband . Indeed, because of its potential for a positive impact on public health, cascade screening for FH has been designated a “Tier 1 Genomics Application” by the Centers for Disease Control and Prevention’s (CDC) Office of Genomics and Precision Public Health .
Unfortunately, in the US, few efforts have been made to develop cascade screening models, and few published reports exist of successful cascade screening programs. Furthermore, in clinical context, the standand of care (i.e. usual care) remains for healthcare providers to counsel FH patients on the importance of their relatives being screened [ , ]. No active efforts are made to ensure relatives are actually screened.
In contrast, several other countries have implemented efforts to ensure relatives get screened . Of these, the Netherlands is widely recognized as having had the most successful national cascade screening program, with over 70% of all individuals with FH identified nationwide [ , ]. In the Dutch model, healthcare providers identified FH probands and, once genetically confirmed to have FH, forwarded their contact information to a centralized coordinating office funded by the government, called the “Foundation for Tracing FH.” The probands, and subsequently their family members, were contacted, family history gathered, and screening visits scheduled. Of note, 90% of FH probands had family members screened for FH. The success of this approach has been linked to several key aspects: engagement with probands and families outside of usual healthcare settings by the “Foundation for Tracing FH,” direct contact with relatives, and in-home visits for sample collection (for laboratory and genetic testing).
To begin assessing whether key aspects of the Dutch model are feasible in the US, we conducted a multi-site single-arm proof-of-concept study. In our study, the US-based FH Foundation directly engaged with FH probands and relatives outside of usual healthcare settings – similar to the “Foundation for Tracing FH” in the Netherlands – to facilitate cascade screening.
All patients gave informed consent with the approval of the Institutional Review Board at the University of Texas Southwestern (UTSW) Medical Center or University of Pennsylvania (UPENN). Inclusion criteria for probands was age ≥ 18 and a diagnosis of FH confirmed by genetic testing. Exclusion criteria included 1) majority of relatives living outside of US, 2) less than two first-degree relatives living, 3) inability to give informed consent. The study ran for 8 weeks.
Study investigators identified and consented FH probands from specialty lipid clinics (UTSW, UPENN) or from individuals actively involved as volunteers with the FH Foundation. Study coordinators from UTSW or UPENN then arranged for telephone or video visits with the proband and the Chief Medical Officer at the FH Foundation. The FH Foundation (Winter Park, Florida), a 501c3 research and advocacy organization, engaged with FH probands during these telephone and video visits, similar to the approach taken by the Dutch “Foundation for Tracing FH.” Specifically, the FH Foundation counseled probands on the importance of family screening for individuals with FH, and a semi-structured set of questions regarding family history (modeled after the Dutch protocol) was used to collect family information (see Supplementary material).
To assess whether our model improved cascade screening in the families enrolled, we asked probands detailed questions regarding which relatives had already been screened for FH. A relative was considered to be screened if they had previously had both lipid measurement and genetic testing. Based on the Dutch experience, both lipid measurement and genetic testing are needed for effective cascade screening as approximately 15% of relatives will harbor pathogenic variants but have normal LDL-C levels [ , ].
Probands were asked by the FH Foundation to contact their first degree relatives and inform them of the study and the need to be screened for FH. Concomitantly, contact information for first-degree relatives was collected by study coordinators to arrange for telephone or video visits with the FH Foundation.
During the calls between relatives and the FH Foundation, discussions focused on the relatives’ risk of having FH, risk of ASCVD, benefits of cholesterol lowering if they were found to be affected, and the benefits and risks of genetic testing. Risks of genetic testing included a description of the US Genetic Information Nondiscrimination Act as well as the exceptions to this act (e.g. life insurance). If the relative agreed, informed consent was taken to enroll in the study for FH screening with both genetic testing and lipid measurements.
Originally, we planned to have local study teams arrange collection of blood or sputum samples from relatives via home visits, site clinic appointments, or mailed blood or sputum kits (for relatives who live away from study sites). Our main outcome variable was the number of families screened. Because of COVID-19 limitations on human research activities, we reduced the scope of our original study design by changing the main outcome from families “screened” to “consented” as blood or saliva samples could not be collected due to restrictions on in-person research visits.
In June and July 2020, we identified 11 unrelated probands with genetically confirmed FH and all 11 agreed to participate ( Table 1 ). Mean age was 43 years; 82% were women, and 82% were of European ancestry.
|Characteristic of probands|
|Age, probands, years||45 (30–79)|
|Women, n||9 (82%)|
|European Ancestry||9 (82%)|
|African American||1 (9%)|
|Preferred method(s) of communication|
|Number of living 1st degree relatives per family||4 (2–8)|
|1st degree relatives already screened for FH per family *||0 (0–2)|
|Characteristics of relatives|
|Total relatives contacted, n||9|
|# families with any relatives consented, n||6 (55%)|
|# famlies with at least 2 relatives consented||3|
|Age, years||46 (6–75)|
|Women, n||5 (56%)|