Yield of Familial Hypercholesterolemia Genetic and Phenotypic Diagnoses After Electronic Health Record and Genomic Data Screening.

Background Data mining of electronic health records to identify patients suspected of familial hypercholesterolemia (FH) has been limited by absence of both phenotypic and genomic data in the same cohort. Methods and Results Using the Geisinger MyCode Community Health Initiative cohort (n=130 257), we ran 2 screening algorithms (Mayo Clinic [Mayo] and flag, identify, network, deliver [FIND] FH) to determine FH genetic and phenotypic diagnostic yields. With 29 243 excluded by Mayo (for secondary causes of hypercholesterolemia, no lipid value in electronic health records), 52 034 excluded by FIND FH (insufficient data to run the model), and 187 excluded for prior FH diagnosis, a final cohort of 59 729 participants was created. Genetic diagnosis was based on presence of a pathogenic or likely pathogenic variant in FH genes. Charts from 180 variant-negative participants (60 controls, 120 identified by FIND FH and Mayo) were reviewed to calculate Dutch Lipid Clinic Network scores; a score ≥5 defined probable phenotypic FH. Mayo flagged 10 415 subjects; 194 (1.9%) had a pathogenic or likely pathogenic FH variant. FIND FH flagged 573; 34 (5.9%) had a pathogenic or likely pathogenic variant, giving a net yield from both of 197 out of 280 (70%). Confirmation of a phenotypic diagnosis was constrained by lack of electronic health record data on physical findings or family history. Phenotypic FH by chart review was present by Mayo and/or FIND FH in 13 out of 120 versus 2 out of 60 not flagged by either (P<0.09). Conclusions Applying 2 recognized FH screening algorithms to the Geisinger MyCode Community Health Initiative identified 70% of those with a pathogenic or likely pathogenic FH variant. Phenotypic diagnosis was rarely achievable due to missing data.

Patient experiences align with the familial hypercholesterolemia global call to action.

Objective: To explore alignment of perspectives from individuals and families with familial hypercholesterolemia (FH) to the FH Global Call to Action recommendations. Methods: Interviews and focus groups were conducted with individuals and families with FH from multiple U.S. health systems and the Family Heart Foundation community to capture lived experiences and to identify barriers to diagnosis, cascade testing, and treatment. Participant perspectives were examined and classified, according to their alignment to recommendations of the FH Global Call to Action. Results: A total of 75 lived experiences were analyzed. Participants were majority female, mostly white, older, and well-educated. Participants most frequently mentioned recommendations were family-based care (84%) and screening, testing, & diagnosis (84%), followed by treatment (69%), advocacy (60%), cost & value (59%), awareness (56%), research & registries (43%), and severe & homozygous FH (11%). An average of 4.65 (SD 1.76) recommendations were mentioned. Conclusions: The FH Global Call to Action was driven by the persistent unmet needs of those living with FH in receiving a timely diagnosis, appropriate care, and support to prevent early morbidity and mortality. Patient- and family-centric perspectives suggest the FH Global Call to Action captures these concerns. Acting on recommendations, particularly improvements in screening and family-based care, will address patient, and public health, concerns.

A proof-of-concept study of cascade screening for Familial Hypercholesterolemia in the US, adapted from the Dutch model.

BACKGROUND: 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). METHODS: 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." RESULTS: 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. CONCLUSIONS: 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.

Women Living with Familial Hypercholesterolemia: Challenges and Considerations Surrounding Their Care.

PURPOSE OF REVIEW: To highlight the gender-based differences in presentation and disparities in care for women with familial hypercholesterolemia (FH). RECENT FINDINGS: Women with FH experience specific barriers to care including underrepresentation in research, significant underappreciation of risk, and interrupted therapy during childbearing. National and international registry and clinical trial data show significant healthcare disparities for women with FH. Women with FH are less likely to be on guideline-recommended high-intensity statin medications and those placed on statins are more likely to discontinue them within their first year. Women with FH are also less likely to be on regimens including non-statin agents such as PCSK9 inhibitors. As a result, women with FH are less likely to achieve target low-density lipoprotein cholesterol (LDL-C) targets, even those with prior atherosclerotic cardiovascular disease (ASCVD). FH is common, under-diagnosed, and under-treated. Disparities of care are more pronounced in women than men. Additionally, FH weighs differently on women throughout the course of their lives starting from choosing contraceptives as young girls along with lipid-lowering therapy, timing pregnancy, choosing breastfeeding or resumption of therapy, and finally deciding goals of care during menopause. Early identification and appropriate treatment prior to interruptions of therapy for childbearing can lead to marked reduction in morbidity and mortality. Women access care differently than men and increasing awareness among all providers, especially cardio-obstetricians, may improve diagnostic rates. Understanding the unique challenges women with FH face is crucial to close the gaps in care they experience.

Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia: A Global Call to Action.

Importance: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. Observations: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. Conclusions and Relevance: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.

ClinVar database of global familial hypercholesterolemia-associated DNA variants.

Accurate and consistent variant classification is imperative for incorporation of rapidly developing sequencing technologies into genomic medicine for improved patient care. An essential requirement for achieving standardized and reliable variant interpretation is data sharing, facilitated by a centralized open-source database. Familial hypercholesterolemia (FH) is an exemplar of the utility of such a resource: it has a high incidence, a favorable prognosis with early intervention and treatment, and cascade screening can be offered to families if a causative variant is identified. ClinVar, an NCBI-funded resource, has become the primary repository for clinically relevant variants in Mendelian disease, including FH. Here, we present the concerted efforts made by the Clinical Genome Resource, through the FH Variant Curation Expert Panel and global FH community, to increase submission of FH-associated variants into ClinVar. Variant-level data was categorized by submitter, variant characteristics, classification method, and available supporting data. To further reform interpretation of FH-associated variants, areas for improvement in variant submissions were identified; these include a need for more detailed submissions and submission of supporting variant-level data, both retrospectively and prospectively. Collaborating to provide thorough, reliable evidence-based variant interpretation will ultimately improve the care of FH patients.

Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.

Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.

Delivery Of Cascade Screening For Hereditary Conditions: A Scoping Review Of The Literature.

Cascade screening is the process of contacting relatives of people who have been diagnosed with certain hereditary conditions. Its purpose is to identify, inform, and manage those who are also at risk. We conducted a scoping review to obtain a broad overview of cascade screening interventions, facilitators and barriers to their use, relevant policy considerations, and future research needs. We searched for relevant peer-reviewed literature in the period 1990-2017 and reviewed 122 studies. Finally, we described 45 statutes and regulations related to the use and release of genetic information across the fifty states. We sought standardized best practices for optimizing cascade screening across various geographic and policy contexts, but we found none. Studies in which trained providers contacted relatives directly, rather than through probands (index patients), showed greater cascade screening uptake; however, policies in some states might limit this approach. Major barriers to cascade screening delivery include suboptimal communication between the proband and family and geographic barriers to obtaining genetic services. Few US studies examined interventions for cascade screening or used rigorous study designs such as randomized controlled trials. Moving forward, there remains an urgent need to conduct rigorous intervention studies on cascade screening in diverse US populations, while accounting for state policy considerations.