Kochan, David C.

Introduction: Prior reports of the genetic etiology of hypercholesterolemia are affected by referral bias, inclusion of individuals with secondary hypercholesterolemia and variability in identifying pathogenic variants. We sought to assess the prevalence of monogenic and polygenic etiologies in a community based cohort of adults with primary hypercholesterolemia (LDL-C ≥155 mg/dL after excluding secondary causes). Methods: We identified 1719 individuals aged 18-70 years with primary hypercholesterolemia from SE Minnesota. The Dutch Lipid Clinic Network (DLCN) score was ascertained by an electronic health record (EHR) based algorithm followed by manual review. Familial hypercholesterolemia (FH) was considered present with a DLCN score ≥6 whereas a DLCN score of 3-5 was considered possible FH. Participants underwent sequencing of FH genes ( LDLR, APOB, PCSK9 ) and genotyping of 12 SNPs known to be associated with LDL-C. Rare (frequency <0.1%) and putatively functional variants were identified and pathogenicity was assigned based on the ACMG guidelines using relevant database, literature and EHR review. A polygenic score (PGS) for LDL-C (derived from 12 SNPs) >90 th percentile was considered an indicator of polygenic etiology. Results: A pathogenic/likely pathogenic variant (16 in LDLR , 1in APOB and 2 in PCSK9 ) was present in 24 (1.3%) individuals, a PGS >90 th percentile was present in 265 (15.4%) and 4 (0.2%) had both a monogenic and polygenic etiology. The overall prevalence of an identifiable genetic etiology was 17%. Based on clinical criteria the overall prevalence of FH (DLCN ≥6) was 7.0% (6.1% probable and 0.9% definite) and that of possible FH was 30.0%. In the possible, probable and definite FH categories, a monogenic etiology was present in 2.4%, 9.5% and 26.7% and a polygenic etiology in 19.1%, 21.0% and 13.3% respectively. 52.0% of those with a monogenic etiology and 9.7% of those with a polygenic etiology met the DLCN criteria for FH. Conclusions: This study provides for the first time estimates of monogenic and polygenic etiology of hypercholesterolemia in adults from the community, excluding cases of secondary hypercholesterolemia and using standardized methods of variant annotation.

Introduction: Relatively little is known about outcomes following return of secondary findings detected in large scale sequencing projects. We assessed 1-year outcomes following return of pathogenic/likely pathogenic (P/LP) variants associated with familial hypercholesterolemia (FH) in phase III of the eMERGE network (2015-2019). Methods: Adult participants (n=18,544) at 7 sites were enrolled in a prospective cohort study to study the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . Process, intermediate, and/or clinical outcomes within 1-year after return of results (RoR) were ascertained by electronic health record (EHR) review. A process outcome was defined as referral to a specialist or ordering new tests, including lipid profile and screening tests for coronary heart disease. An intermediate outcome was defined as new diagnosis of FH or atherosclerotic cardiovascular disease. A clinical outcome was defined as initiation or change in lipid-lowering medication. The primary outcomes were a new diagnosis of FH and modification of lipid lowering therapy. Results: Results were returned to 134 individuals, and data for 119 participants were available for the outcomes analysis. Process (86%), intermediate (49%), and/or clinical (26%) outcomes occurred in 92% of participants. Process outcomes included 72% with new tests ordered and 61% referred to a specialist. Before RoR, 86.5% of individuals with FH associated P/LP variants had a diagnosis of hypercholesterolemia but only 17.6% had a diagnosis of FH; 89% were on a statin but only 58% were on a high intensity statin. Following RoR, 44% (52/119) received a new diagnosis of FH. Lipid lowering treatment was modified in 26% (31/119), including initiation of a statin in 5%, increasing statin dose in 13%, and adding ezetimibe or a PCSK9 inhibitor in 12.6%. Conclusions: In a multisite cohort of EHR-linked biobanks, monogenic FH was underdiagnosed (only 17.6% had a specific diagnosis) and undertreated (only 58% were on a high intensity statin); 44% of participants received a new diagnosis of FH and 26% had lipid lowering treatment modified after RoR. These results highlight the clinical utility of returning FH variants in EHR-linked biobanks.

Background: The implications of secondary findings detected in large-scale sequencing projects remain uncertain. We assessed prevalence and penetrance of pathogenic familial hypercholesterolemia (FH) variants, their association with coronary heart disease (CHD), and 1-year outcomes following return of results in phase III of the electronic medical records and genomics network. Methods: Adult participants (n=18 544) at 7 sites were enrolled in a prospective cohort study to assess the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . FH variant prevalence and penetrance (defined as low-density lipoprotein cholesterol >155 mg/dL) were estimated after excluding participants enrolled on the basis of hypercholesterolemia. Multivariable logistic regression was used to estimate the odds of CHD compared to age- and sex-matched controls without FH-associated variants. Process (eg, referral to a specialist or ordering new tests), intermediate (eg, new diagnosis of FH), and clinical (eg, treatment modification) outcomes within 1 year after return of results were ascertained by electronic health record review. Results: The prevalence of FH-associated pathogenic variants was 1 in 188 (69 of 13,019 unselected participants). Penetrance was 87.5%. The presence of an FH variant was associated with CHD (odds ratio, 3.02 [2.00–4.53]) and premature CHD (odds ratio, 3.68 [2.34–5.78]). At least 1 outcome occurred in 92% of participants; 44% received a new diagnosis of FH and 26% had treatment modified following return of results. Conclusions: In a multisite cohort of electronic health record–linked biobanks, monogenic FH was prevalent, penetrant, and associated with presence of CHD. Nearly half of participants with an FH-associated variant received a new diagnosis of FH and a quarter had treatment modified after return of results. These results highlight the potential utility of sequencing electronic health record–linked biobanks to detect FH.

A challenge in returning genomic test results to research participants is how best to communicate complex and clinically nuanced findings to participants in a manner that is scalable to the large numbers of participants enrolled. The purpose of this study was to examine the features of genetic results letters produced at each Electronic Medical Records and Genomics (eMERGE3) Network site to assess their readability and content. Letters were collected from each site, and a qualitative analysis of letter content and a quantitative analysis of readability statistics were performed. Because letters were produced independently at each eMERGE site, significant heterogeneity in readability and content was found. The content of letters varied widely from a baseline of notifying participants that results existed to more detailed information about positive or negative results, as well as materials for sharing with family members. Most letters were significantly above the Centers for Disease Control-suggested reading level for health communication. While continued effort should be applied to make letters easier to understand, the ongoing challenge of explaining complex genomic information, the implications of negative test results, and the uncertainty that comes with some types of test and result makes simplifying letter text challenging.

Familial Hypercholesterolemia (FH) is an inherited disorder associated with increased cardiovascular risk that requires patients to make multiple impactful decisions regarding the management of their condition. Patient decision aids (PDAs) can facilitate shared decision-making (SDM) and enable patients to make choices that are concordant with their goals and values. To inform the development of a PDA for patients with FH, we employed a qualitative inductive approach and focus group discussions with patients, physicians, and genetic counselors. We explored and analyzed the perceptions and understanding of these stakeholders related to a PDA for FH and identified important concepts to include in the PDA. Categories emerging from focus group discussions included: (a) perceptions of a PDA related to FH; (b) discussion about the content of a PDA related to FH; and (c) SDM. In general, stakeholders were in favor of developing tools which can inform and individualize discussion about genetic testing and treatment options for FH. Physicians valued a tool that facilitates knowledge transfer to FH patients. Patients desired a tool to help them understand the genetic aspects of and treatment options related to FH. Genetic counselors emphasized the inclusion of visual aids to support discussion with patients. Potential barriers to and facilitators of PDA implementation were identified. The input of various stakeholders will inform the development of a prototype tool that will be iteratively tested before implementation in the clinical setting.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site’s research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10–261 days, 0–11, and 11–90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.