A Model for Genome-First Care: Returning Secondary Genomic Findings to Participants and Their Healthcare Providers in a Large Research Cohort.

There is growing interest in communicating clinically relevant DNA sequence findings to research participants who join projects with a primary research goal other than the clinical return of such results. Since Geisinger's MyCode Community Health Initiative (MyCode) was launched in 2007, more than 200,000 participants have been broadly consented for discovery research. In 2013 the MyCode consent was amended to include a secondary analysis of research genomic sequences that allows for delivery of clinical results. Since May 2015, pathogenic and likely pathogenic variants from a set list of genes associated with monogenic conditions have prompted "genome-first" clinical encounters. The encounters are described as genome-first because they are identified independent of any clinical parameters. This article (1) details our process for generating clinical results from research data, delivering results to participants and providers, facilitating condition-specific clinical evaluations, and promoting cascade testing of relatives, and (2) summarizes early results and participant uptake. We report on 542 participants who had results uploaded to the electronic health record as of February 1, 2018 and 291 unique clinical providers notified with one or more participant results. Of these 542 participants, 515 (95.0%) were reached to disclose their results and 27 (5.0%) were lost to follow-up. We describe an exportable model for delivery of clinical care through secondary use of research data. In addition, subject and provider participation data from the initial phase of these efforts can inform other institutions planning similar programs.

Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource.

With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: "Definitive," "Strong," "Moderate," "Limited," "No Reported Evidence," or "Conflicting Evidence." Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.

Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis.

Mechanotransduction, the pathway by which mechanical forces are translated to biological signals, plays important but poorly characterized roles in physiology. PIEZOs are recently identified, widely expressed, mechanically activated ion channels that are hypothesized to play a role in mechanotransduction in mammals. Here, we describe two distinct PIEZO2 mutations in patients with a subtype of Distal Arthrogryposis Type 5 characterized by generalized autosomal dominant contractures with limited eye movements, restrictive lung disease, and variable absence of cruciate knee ligaments. Electrophysiological studies reveal that the two PIEZO2 mutations affect biophysical properties related to channel inactivation: both E2727del and I802F mutations cause the PIEZO2-dependent, mechanically activated currents to recover faster from inactivation, while E2727del also causes a slowing of inactivation. Both types of changes in kinetics result in increased channel activity in response to a given mechanical stimulus, suggesting that Distal Arthrogryposis Type 5 can be caused by gain-of-function mutations in PIEZO2. We further show that overexpression of mutated PIEZO2 cDNAs does not cause constitutive activity or toxicity to cells, indicating that the observed phenotype is likely due to a mechanotransduction defect. Our studies identify a type of channelopathy and link the dysfunction of mechanically activated ion channels to developmental malformations and joint contractures.

Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays.

We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements of ~5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease.

Comparing electronic health record portals to obtain patient-entered family health history in primary care.

BACKGROUND: There is growing interest in developing systems to overcome barriers for acquiring and interpreting family health histories in primary care. OBJECTIVE: To examine the capacity of three different electronic portals to collect family history from patients and deposit valid data in an electronic health record (EHR). DESIGN: Pilot trial. PARTICIPANTS, INTERVENTION: Patients were enrolled from four primary care practices and were asked to collect family health history before a physical exam using either telephone-based interactive voice response (IVR) technology, a secure Internet portal, or a waiting room laptop computer, with portal assigned by practice. Intervention practices were compared to a "usual care" practice, where there was no standard workflow to document family history (663 participants in the three intervention arms were compared to 296 participants from the control practice). MAIN MEASURES: New documentation of any family history in a coded EHR field within 30 days of the visit. Secondary outcomes included participation rates and validity. KEY RESULTS: Demographics varied by clinic. Documentation of new family history data was significantly higher, but modest, in each of the three intervention clinics (7.5 % for IVR clinic, 20.3 % for laptop clinic, and 23.1 % for patient portal clinic) versus the control clinic (1.7 %). Patient-entered data on common conditions in first degree relatives was confirmed as valid by a genetic counselor for the majority of cases (ranging from 64 to 82 % in the different arms). CONCLUSIONS: Within primary care practices, valid patient entered family health history data can be obtained electronically at higher rates than a standard of care that depends on provider-entered data. Further research is needed to determine how best to match different portals to individual patient preference, how the tools can best be integrated with provider workflow, and to assess how they impact the use of screening and prevention.

Obtaining a Genetic Family History Using Computer-Based Tools.

Family health history has long been known to be a powerful predictor of individual disease risk. It can be obtained prior to DNA sequencing in order to examine inheritance patterns, to be used as a proxy for genetic information, or as a tool to guide decision-making on the utility of diagnostic genetic testing. Increasingly, it is also being obtained retrospectively from sequenced individuals to examine familial disease penetrance and to identify at-risk relatives for cascade testing. The collection of adequate family history information to screen patients for disease risk and guide decision-making is a time-consuming process that is difficult to accomplish exclusively through discussion between patients and their providers. Engaging individuals and families in data collection and data entry has the potential to improve data accuracy through re-iterative review with family members and health care providers, and to empower patients in their healthcare. In addition, electronic datasets can be shared amongst relatives and stored in electronic health records or personal files, enabling portability of family history information. The U.S. Surgeon General, the Centers for Disease Control and Prevention (CDC), and others have developed tools for electronic family history collection to help families and providers obtain this useful information in an efficient manner. This unit describes the utility of the web-based My Family Health Portrait (https://familyhistory.hhs.gov) as the prototype for patient-entered family history. © 2018 by John Wiley & Sons, Inc.

Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants.

Importance: Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals. Objectives: To identify pathogenic and likely pathogenic (P/LP) BRCA1/2 variants in an unselected research cohort, and to characterize the features associated with P/LP variants. Design, Setting, and Participants: This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (Geisinger Health System, Danville, Pennsylvania) from January 1, 2014, to March 1, 2016. Participants are part of the DiscovEHR cohort and were identified through the Geisinger MyCode Community Health Initiative. They consented to a research protocol that included sequencing and return of actionable test results. Clinical data from electronic health records and clinical visits were correlated with variants. Comparisons were made between those with (cases) and those without (controls) P/LP variants in BRCA1/2. Main Outcomes: Prevalence of P/LP BRCA1/2 variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among BRCA1/2 variant carriers and noncarriers. Results: Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic BRCA1/2 variants and 267 (0.5%) were BRCA1/2 carriers. Of the 267 cases (148 [55.4%] were women and 119 [44.6%] were men with a mean [range] age of 58.9 [23-90] years), 183 (68.5%) received clinically confirmed results in their electronic health record. Among the 267 participants with P/LP BRCA1/2 variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had BRCA1 variants, and 172 (64.4%) had BRCA2 variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased BRCA1/2 carriers and in 56 (20.9%) of all 267 BRCA1/2 carriers. Among women, 31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers (odds ratio [OR], 5.95; 95% CI, 3.88-9.13; P < .001). Ovarian cancer history was present in 15 (10.1%) of 148 variant carriers and in 195 (0.6%) of 29 880 variant noncarriers (OR, 18.30; 95% CI, 10.48-31.4; P < .001). Among 89 BRCA1/2 carriers without prior testing but with comprehensive personal and family history data, 44 (49.4%) did not meet published guidelines for clinical testing. Conclusions and Relevance: This study found that compared with previous clinical care, exome sequencing-based screening identified 5 times as many individuals with P/LP BRCA1/2 variants. These findings suggest that genomic screening may identify BRCA1/2-associated cancer risk that might otherwise remain undetected within health care systems and may provide opportunities to reduce morbidity and mortality in patients.

Genetic identification of familial hypercholesterolemia within a single U.S. health care system.

Familial hypercholesterolemia (FH) remains underdiagnosed despite widespread cholesterol screening. Exome sequencing and electronic health record (EHR) data of 50,726 individuals were used to assess the prevalence and clinical impact of FH-associated genomic variants in the Geisinger Health System. The estimated FH prevalence was 1:256 in unselected participants and 1:118 in participants ascertained via the cardiac catheterization laboratory. FH variant carriers had significantly increased risk of coronary artery disease. Only 24% of carriers met EHR-based presequencing criteria for probable or definite FH diagnosis. Active statin use was identified in 58% of carriers; 46% of statin-treated carriers had a low-density lipoprotein cholesterol level below 100 mg/dl. Thus, we find that genomic screening can prompt the diagnosis of FH patients, most of whom are receiving inadequate lipid-lowering therapy.

Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study.

The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.

BACKGROUND: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

The application of computer-based tools in obtaining the genetic family history.

Family health history is both an adjunct to and a focus of current genetic research, having long been known to be a powerful predictor of individual disease risk. As such, it has been primarily used as a proxy for genetic information. Over the past decade, new roles for family history have emerged, perhaps most importantly as a primary tool for guiding decision-making on the use of expensive genetic testing. The collection of family history information is an important but time-consuming process. Efforts to engage the patient or research subject in preliminary data collection have the potential to improve data accuracy and allow clinicians and researchers more time for analytic tasks. The U.S. Surgeon General, the Centers for Disease Control and Prevention (CDC), and others have developed tools for electronic family history collection. This unit describes the utility of the Web-based My Family Health Portrait (https://familyhistory.hhs.gov) as the prototype for patient-entered family history.

Health-care referrals from direct-to-consumer genetic testing.

BACKGROUND: direct-to-consumer genetic testing (DTC-GT) provides personalized genetic risk information directly to consumers. Little is known about how and why consumers then communicate the results of this testing to health-care professionals. AIM: to query specialists in clinical genetics about their experience with individuals who consulted them after DTC-GT. METHODS: invitations to participate in a questionnaire were sent to three different groups of genetic professionals, totaling 4047 invitations, asking questions about individuals who consulted them after DTC-GT. For each case reported, respondents were asked to describe how the case was referred to them, the patient's rationale for DTC-GT, and the type of DTC-GT performed. Respondents were also queried about the consequences of the consultations in terms of additional testing ordered. The costs associated with each consultation were estimated. A clinical case series was compiled based upon clinician responses. RESULTS: the invitation resulted in 133 responses describing 22 cases of clinical interactions following DTC-GT. Most consultations (59.1%) were self-referred to genetics professionals, but 31.8% were physician referred. Among respondents, 52.3% deemed the DTC-GT to be "clinically useful." BRCA1/2 testing was considered clinically useful in 85.7% of cases; 35.7% of other tests were considered clinically useful. Subsequent referrals from genetics professionals to specialists and/or additional diagnostic testing were common, generating individual downstream costs estimated to range from $40 to $20,600. CONCLUSIONS: this clinical case series suggests that approximately half of clinical geneticists who saw patients after DTC-GT judged that testing was clinically useful, especially the BRCA1/2 testing. Further studies are needed in larger and more diverse populations to better understand the interactions between DTC-GT and the health-care system.