Implementing Evidence-Based Assertions of Clinical Actionability in the Context of Secondary Findings: Updates from the ClinGen Actionability Working Group.

PURPOSE: The ClinGen Actionability Working Group (AWG) developed an evidence-based framework to generate actionability reports and scores of gene-condition pairs in the context of secondary findings from genome sequencing. Here we describe the expansion of the framework to include actionability assertions. METHODS: Initial development of the actionability rubric was based on previously scored adult gene-condition pairs and individual expert evaluation. Rubric refinement was iterative and based on evaluation, feedback, and discussion. The final rubric was pragmatically evaluated via integration into actionability assessments for 27 gene-condition pairs. RESULTS: The resulting rubric has a four-point scale (limited, moderate, strong, definitive) and uses the highest-scoring outcome-intervention pair of each gene-condition pair to generate a preliminary assertion. During AWG discussions, pre-defined criteria and factors guide discussion to produce a consensus assertion for a gene-condition pair, which may differ from the preliminary assertion. The AWG has retrospectively generated assertions for all previously scored gene-condition pairs and are prospectively asserting on gene-condition pairs under assessment, having completed over 170 adult and 188 pediatric gene-condition pairs. CONCLUSION: The AWG expanded its framework to provide actionability assertions to enhance the clinical value of their resources and increase their utility as decision aids regarding return of secondary findings.

Correction: Foss et al. The Rise of Population Genomic Screening: Characteristics of Current Programs and the Need for Evidence Regarding Optimal Implementation. J. Pers. Med. 2022, 12, 692.

There was an error in the original publication [...].

Reflections on 'common' genetic medical history questions: Time to examine the what, why, and how.

OBJECTIVE: A central goal of patient-centered care is to establish a therapeutic relationship. While remaining in tune with patient emotions, genetics providers must ask questions to understand medical histories that will inform the differential diagnosis, evaluation plan, and potential treatments. METHODS: 195 audio-recorded conversations between providers and caregivers of pediatric patients with suspected genetic conditions were coded and analyzed. Coders identified sensitive history-taking questions asked by providers related to exposures and complications during pregnancy; ancestry and consanguinity; educational attainment of the caregiver; and family structure. RESULTS: We highlight examples of providers: using stigmatizing language about conception or consanguinity; not clarifying the intent behind questions related to caregivers' educational attainment and work history; and making presumptions or assumptions about caregivers' race and ethnicity, family structure, and exposures during pregnancy. CONCLUSION: Some questions and phrasing considered routine by genetics providers may interfere with patient-centered care by straining attempts to establish a therapeutic, trusting relationship. Additional research is needed to assess how question asking and phrasing impact rapport building and patient experience during genetics encounters. PRACTICE IMPLICATIONS: Review of the purpose and need for medical history questions common to genetics practice could serve to improve patient-centered care.

Question prompt lists and caregiver question asking in pediatric specialty appointments: A randomized controlled trial.

OBJECTIVE: Question prompt lists (QPLs) have been effective at increasing patient involvement and question asking in medical appointments, which is critical for shared decision making. We investigated whether pre-visit preparation (PVP), including a QPL, would increase question asking among caregivers of pediatric patients with undiagnosed, suspected genetic conditions. METHODS: Caregivers were randomized to receive the PVP before their appointment (n = 59) or not (control, n = 53). Appointments were audio-recorded. Transcripts were analyzed to determine questions asked. RESULTS: Caregivers in the PVP group asked more questions (MeanPVP = 4.36, SDPVP = 4.66 vs. Meancontrol = 2.83, SDcontrol = 3.03, p = 0.045), including QPL questions (MeanPVP = 1.05, SDPVP = 1.39 vs. Meancontrol = 0.36, SDcontrol = 0.81, p = 0.002). Caregivers whose child had insurance other than Medicaid in the PVP group asked more total and QPL questions than their counterparts in the control group (ps = 0.005 and 0.002); there was no intervention effect among caregivers of children with Medicaid or no insurance (ps = 0.775 and 0.166). CONCLUSION: The PVP increased question asking but worked less effectively among traditionally underserved groups. Additional interventions, including provider-focused efforts, may be needed to promote engagement of underserved patients. PRACTICE IMPLICATIONS: Patient/family-focused interventions may not be beneficial for all populations. Providers should be aware of potential implicit and explicit biases and encourage question asking to promote patient/family engagement.

The Burden of COVID-19 on Caregivers of Children with Suspected Genetic Conditions: A Therapeutic Odyssey.

AIMS: Children with disabilities and rare or undiagnosed conditions and their families have faced numerous hardships of living during the COVID-19 pandemic. For those with undiagnosed conditions, the diagnostic odyssey can be long, expensive, and marked by uncertainty. We, therefore, sought to understand whether and how COVID-19 impacted the trajectory of children's care. METHODS: We conducted semi-structured qualitative interviews with 25 caregivers who, prior to the pandemic, were on a diagnostic odyssey for their children. RESULTS: Most caregivers did not report any interruptions to their child's diagnostic odyssey. The greatest impact was access to therapy services, including the suspension or loss of their child's in-person therapeutic care and difficulties with virtual therapies. This therapy gap caused caregivers to fear that their children were not making progress. CONCLUSION: Although much has been written about the challenges of diagnostic odysseys for children and their families, this study illustrates the importance of expanding the focus of these studies to include therapeutic odysseys. Because therapeutic odysseys continue regardless of whether diagnoses are made, future research should investigate how to support caregivers through children's therapies within and outside of the COVID-19 context.

The Rise of Population Genomic Screening: Characteristics of Current Programs and the Need for Evidence Regarding Optimal Implementation.

PURPOSE: Advances in clinical genomic sequencing capabilities, including reduced costs and knowledge gains, have bolstered the consideration of genomic screening in healthy adult populations. Yet, little is known about the existing landscape of genomic screening programs in the United States. It can be difficult to find information on current implementation efforts and best practices, particularly in light of critical questions about equity, cost, and benefit. METHODS: In 2020, we searched publicly available information on the Internet and the scientific literature to identify programs and collect information, including: setting, program funding, targeted population, test offered, and patient cost. Program representatives were contacted throughout 2020 and 2021 to clarify, update, and supplement the publicly available information. RESULTS: Twelve programs were identified. Information was available on key program features, such as setting, genes tested, and target populations. Data on costs, outcomes, or long-term sustainability plans were not always available. Most programs offered testing at no or significantly reduced cost due to generous pilot funding, although the sustainability of these programs remains unknown. Gene testing lists were diverse, ranging from 11 genes (CDC tier 1 genes) to 59 genes (ACMG secondary findings list v.2) to broad exome and genome sequencing. This diversity presents challenges for harmonized data collection and assessment of program outcomes. CONCLUSIONS: Early programs are exploring the logistics and utility of population genomic screening in various settings. Coordinated efforts are needed to take advantage of data collected about uptake, infrastructure, and intervention outcomes to inform future research, evaluation, and program development.

Integration of stakeholder engagement from development to dissemination in genomic medicine research: Approaches and outcomes from the CSER Consortium.

PURPOSE: There is a critical need for genomic medicine research that reflects and benefits socioeconomically and ancestrally diverse populations. However, disparities in research populations persist, highlighting that traditional study designs and materials may be insufficient or inaccessible to all groups. New approaches can be gained through collaborations with patient/community stakeholders. Although some benefits of stakeholder engagement are recognized, routine incorporation into the design and implementation of genomics research has yet to be realized. METHODS: The National Institutes of Health-funded Clinical Sequencing Evidence-Generating Research (CSER) consortium required stakeholder engagement as a dedicated project component. Each CSER project planned and carried out stakeholder engagement activities with differing goals and expected outcomes. Examples were curated from each project to highlight engagement strategies and outcomes throughout the research lifecycle from development through dissemination. RESULTS: Projects tailored strategies to individual study needs, logistical constraints, and other challenges. Lessons learned include starting early with engagement efforts across project stakeholder groups and planned flexibility to enable adaptations throughout the project lifecycle. CONCLUSION: Each CSER project used more than 1 approach to engage with relevant stakeholders, resulting in numerous adaptations and tremendous value added throughout the full research lifecycle. Incorporation of community stakeholder insight improves the outcomes and relevance of genomic medicine research.

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

BACKGROUND: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. RESULTS: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. CONCLUSIONS: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org.

Examining access to care in clinical genomic research and medicine: Experiences from the CSER Consortium.

INTRODUCTION: Ensuring equitable access to health care is a widely agreed-upon goal in medicine, yet access to care is a multidimensional concept that is difficult to measure. Although frameworks exist to evaluate access to care generally, the concept of "access to genomic medicine" is largely unexplored and a clear framework for studying and addressing major dimensions is lacking. METHODS: Comprised of seven clinical genomic research projects, the Clinical Sequencing Evidence-Generating Research consortium (CSER) presented opportunities to examine access to genomic medicine across diverse contexts. CSER emphasized engaging historically underrepresented and/or underserved populations. We used descriptive analysis of CSER participant survey data and qualitative case studies to explore anticipated and encountered access barriers and interventions to address them. RESULTS: CSER's enrolled population was largely lower income and racially and ethnically diverse, with many Spanish-preferring individuals. In surveys, less than a fifth (18.7%) of participants reported experiencing barriers to care. However, CSER project case studies revealed a more nuanced picture that highlighted the blurred boundary between access to genomic research and clinical care. Drawing on insights from CSER, we build on an existing framework to characterize the concept and dimensions of access to genomic medicine along with associated measures and improvement strategies. CONCLUSIONS: Our findings support adopting a broad conceptualization of access to care encompassing multiple dimensions, using mixed methods to study access issues, and investing in innovative improvement strategies. This conceptualization may inform clinical translation of other cutting-edge technologies and contribute to the promotion of equitable, effective, and efficient access to genomic medicine.

Evaluating the clinical utility of early exome sequencing in diverse pediatric outpatient populations in the North Carolina Clinical Genomic Evaluation of Next-generation Exome Sequencing (NCGENES) 2 study: a randomized controlled trial.

BACKGROUND: Exome sequencing (ES) has probable utility for shortening the diagnostic odyssey of children with suspected genetic disorders. This report describes the design and methods of a study evaluating the potential of ES as a routine clinical tool for pediatric patients who have suspected genetic conditions and who are in the early stages of the diagnostic odyssey. METHODS: The North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing (NCGENES) 2 study is an interdisciplinary, multi-site Phase III randomized controlled trial of two interventions: educational pre-visit preparation (PVP) and offer of first-line ES. In this full-factorial design, parent-child dyads are randomly assigned to one of four study arms (PVP + usual care, ES + usual care, PVP + ES + usual care, or usual care alone) in equal proportions. Participants are recruited from Pediatric Genetics or Neurology outpatient clinics in three North Carolina healthcare facilities. Eligible pediatric participants are < 16 years old and have a first visit to a participating clinic, a suspected genetic condition, and an eligible parent/guardian to attend the clinic visit and complete study measures. The study oversamples participants from underserved and under-represented populations. Participants assigned to the PVP arms receive an educational booklet and question prompt list before clinical interactions. Randomization to offer of first-line ES is revealed after a child's clinic visit. Parents complete measures at baseline, pre-clinic, post-clinic, and two follow-up timepoints. Study clinicians provide phenotypic data and complete measures after the clinic visit and after returning results. Reportable study-related research ES results are confirmed in a CLIA-certified clinical laboratory. Results are disclosed to the parent by the clinical team. A community consultation team contributed to the development of study materials and study implementation methods and remains engaged in the project. DISCUSSION: NCGENES 2 will contribute valuable knowledge concerning technical, clinical, psychosocial, and health economic issues associated with using early diagnostic ES to shorten the diagnostic odyssey of pediatric patients with likely genetic conditions. Results will inform efforts to engage diverse populations in genomic medicine research and generate evidence that can inform policy, practice, and future research related to the utility of first-line diagnostic ES in health care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03548779 . Registered on June 07, 2018.

Burden or benefit? Effects of providing education about and the option to request additional genomic findings from diagnostic exome sequencing: A randomized controlled trial.

OBJECTIVE: Many people prefer to learn secondary or "additional" findings from genomic sequencing, including findings with limited medical actionability. Research has investigated preferences for and effects of learning such findings, but not psychosocial and behavioral effects of receiving education about them and the option to request them, which could be burdensome or beneficial (e.g., causing choice overload or satisfying strong preferences, respectively). METHODS: 335 adults with suspected genetic disorders who had diagnostic exome sequencing in a research study and were randomized to receive either diagnostic findings only (DF; n = 171) or diagnostic findings plus education about additional genomic findings and the option to request them (DF + EAF; n = 164). Assessments occurred after enrollment (Time 1), after return of diagnostic results and-for DF + EAF-the education under investigation (Time 2), and three and six months later (Times 3, 4). RESULTS: Time 2 test-related distress, test-related uncertainty, and generalized anxiety were lower in the DF + EAF group (ps = 0.025-0.043). There were no other differences. CONCLUSIONS: Findings show limited benefits and no harms of providing education about and the option to learn additional findings with limited medical actionability. PRACTICE IMPLICATIONS: Findings can inform recommendations for returning additional findings from genomic sequencing (e.g., to research participants or after commercial testing).

Genomic Sequencing Results Disclosure in Diverse and Medically Underserved Populations: Themes, Challenges, and Strategies from the CSER Consortium.

Genomic sequencing results need to be effectively communicated across all populations and practice settings. Projects in the Clinical Sequencing Evidence-Generating Research (CSER) consortium enroll diverse racial/ethnic and medically underserved participants across various clinical contexts. This article explores a set of CSER results disclosure cases to expand the evidence base on experiences returning genomic results. Case details were collected using a structured set of questions. We identified common themes in the case set, and assessed challenges and strategies in achieving six relevant results disclosure objectives. CSER-affiliated patient/community stakeholder impressions of the findings were solicited via video conference calls. Seventeen cases across six CSER projects were included. Case themes sorted into four categories: (1) factors influencing participant understanding, (2) participant emotional response, (3) disease burden, and (4) logistical challenges. Challenges meeting results disclosure objectives included a lack of dialogue, health literacy level, unexpected findings, and complex concepts. Strategies were consistent with traditional genetic counseling practice, but also highlighted approaches being evaluated in CSER projects. Patient/community stakeholders supported the identified themes and provided additional suggestions to improve patient understanding and engagement. These experiences add valuable insights into adapting genomic results disclosure practices to best serve all patient populations.

Application of a framework to guide genetic testing communication across clinical indications.

BACKGROUND: Genetic information is increasingly relevant across healthcare. Traditional genetic counseling (GC) may limit access to genetic information and may be more information and support than some individuals need. We report on the application and clinical implications of a framework to consistently integrate genetics expertise where it is most useful to patients. METHODS: The Clinical Genome Resource's (ClinGen) Consent and Disclosure Recommendations (CADRe) workgroup designed rubrics to guide pre- and post-genetic test communication. Using a standard set of testing indications, pre- and post-test rubrics were applied to 40 genetic conditions or testing modalities with diverse features, including variability in levels of penetrance, clinical actionability, and evidence supporting a gene-disease relationship. Final communication recommendations were reached by group consensus. RESULTS: Communication recommendations were determined for 478 unique condition-indication or testing-indication pairs. For half of the conditions and indications (238/478), targeted discussions (moderate communication depth) were the recommended starting communication level for pre- and post-test conversations. Traditional GC was recommended pre-test for adult-onset neurodegenerative conditions for individuals with no personal history and post-test for most conditions when genetic testing revealed a molecular diagnosis as these situations are likely higher in complexity and uncertainty. A brief communication approach was recommended for more straightforward conditions and indications (e.g., familial hypercholesterolemia; familial variant testing). CONCLUSIONS: The CADRe recommendations provide guidance for clinicians in determining the depth of pre- and post-test communication, strategically aligning the anticipated needs of patients with the starting communication approach. Shorter targeted discussions or brief communications are suggested for many tests and indications. Longer traditional GC consultations would be reserved for patients with more complex and uncertain situations where detailed information, education, and psychological support can be most beneficial. Future studies of the CADRe communication framework will be essential for determining if CADRe-informed care supports quality patient experience while improving access to genetic information across healthcare.

Actionability of commercial laboratory sequencing panels for newborn screening and the importance of transparency for parental decision-making.

BACKGROUND: Newborn screening aims to identify individual patients who could benefit from early management, treatment, and/or surveillance practices. As sequencing technologies have progressed and we move into the era of precision medicine, genomic sequencing has been introduced to this area with the hopes of detecting variants related to a vastly expanded number of conditions. Though implementation of genomic sequencing for newborn screening in public health and clinical settings is limited, commercial laboratories have begun to offer genomic screening panels for neonates. METHODS: We examined genes listed on four commercial laboratory genomic screening panels for neonates and assessed their clinical actionability using an established age-based semi-quantitative metric to categorize them. We identified genes that were included on multiple panels or distinct between panels. RESULTS: Three hundred and nine genes appeared on one or more commercial panels: 74 (23.9%) genes were included in all four commercial panels, 45 (14.6%) were on only three panels, 76 (24.6%) were on only two panels, and 114 (36.9%) genes were listed on only one of the four panels. Eighty-two genes (26.5%) listed on one or more panels were assessed by our method to be inappropriate for newborn screening and to require additional parental decision-making. Conversely, 249 genes that we previously identified as being highly actionable were not listed on any of the four commercial laboratory genomic screening panels. CONCLUSIONS: Commercial neonatal genomic screening panels have heterogeneous content and may contain some conditions with lower actionability than would be expected for public health newborn screening; conversely, some conditions with higher actionability may be omitted from these panels. The lack of transparency about how conditions are selected suggests a need for greater detail about panel content in order for parents to make informed decisions. The nuanced activity of gene list selection for genomic screening should be iteratively refined with evidence-based approaches to provide maximal benefit and minimal harm to newborns.

A review and definition of 'usual care' in genetic counseling trials to standardize use in research.

The descriptor 'usual care' refers to standard or routine care. Yet, no formal definition exists. The need to define what constitutes usual care arises in clinical research. Often one arm in a trial represents usual care in comparison with a novel intervention. Accordingly, usual care in genetic counseling research appears predominantly in randomized controlled trials. Recent standards for reporting genetic counseling research call for standardization, but do not address usual care. We (1) inventoried all seven studies in the Clinical Sequencing Evidence-Generating Consortium (CSER) about how genetic counseling was conceptualized, conducted, and whether a usual care arm was involved; (2) conducted a review of published randomized control trials in genetic counseling, comparing how researchers describe usual care groups; and (3) reviewed existing professionally endorsed definitions and practice descriptions of genetic counseling. We found wide variation in the content and delivery of usual care. Descriptions frequently detailed the content of usual care, most often noting assessment of genetic risk factors, collecting family histories, and offering testing. A minority included addressing psychological concerns or the risks versus benefits of testing. Descriptions of how care was delivered were vague except for mode and type of clinician, which varied. This significant variation, beyond differences expected among subspecialties, reduces the validity and generalizability of genetic counseling research. Ideally, research reflects clinical practice so that evidence generated can be used to improve clinical outcomes. To address this objective, we propose a definition of usual care in genetic counseling research that merges common elements from the National Society of Genetic Counselors' practice definition, the Reciprocal Engagement Model, and the Accreditation Council for Genetic Counselors' practice-based competencies. Promoting consistent execution of usual care in the design of genetic counseling trials can lead to more consistency in representing clinical care and facilitate the generation of evidence to improve it.

Engaging community stakeholders in research on best practices for clinical genomic sequencing.

Aim: Maximizing the utility and equity of genomic sequencing integration in clinical care requires engaging patients, their families, and communities. The NCGENES 2 study explores the impact of engagement between clinicians and caregivers of children with undiagnosed conditions in the context of a diagnostic genomic sequencing study. Methods: A Community Consult Team (CCT) of diverse parents and advocates for children with genetic and/or neurodevelopmental conditions was formed. Results: Early and consistent engagement with the CCT resulted in adaptations to study protocol and materials relevant to this unique study population. Discussion: This study demonstrates valuable contributions of community stakeholders to inform the implementation of translational genomics research for diverse participants.

Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (∼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.

Referencing BRCA in hereditary cancer risk discussions: In search of an anchor in a sea of uncertainty.

As panel testing and exome sequencing are increasingly incorporated into clinical care, clinicians must grapple with how to communicate the risks and treatment decisions surrounding breast cancer genes beyond BRCA1 and BRCA2. In this paper, we examine clinicians' practice of employing BRCA1 and BRCA2 to help contextualize less certain genetic information regarding cancer risk and the possible implications of this practice for patients within the context of an exome sequencing study, NCGENES. We audio-recorded return of results appointments for 14 women who participated in NCGENES, previously had breast cancer, and were suspected of having a hereditary cancer predisposition. These patients were also interviewed four weeks later regarding their understanding of their results. We found that BRCA1 and BRCA2 were held as the gold standard, where clinicians compared what is known about BRCA to the limited understanding of other breast cancer-related genes. BRCA1 and BRCA2 were used as anchors to shape patients' understandings of genetic knowledge, risk, and management, illustrating how the information clinicians provide to patients may work as an external anchor. Yet, presenting BRCA1 and BRCA2 as a means of scientific reassurance can run the risk of patients conflating knowledge about certainty of risk with degree of risk after receiving a result for a moderate penetrance gene. This can be further complicated by misperceptions of the precision of cancer predictability attributed to these or other described 'cancer genes' in public media.

Genomic knowledge in the context of diagnostic exome sequencing: changes over time, persistent subgroup differences, and associations with psychological sequencing outcomes.

PURPOSE: People undergoing diagnostic genome-scale sequencing are expected to have better psychological outcomes when they can incorporate and act on accurate, relevant knowledge that supports informed decision making. METHODS: This longitudinal study used data from the North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing Study (NCGENES) of diagnostic exome sequencing to evaluate associations between factual genomic knowledge (measured with the University of North Carolina Genomic Knowledge Scale at three assessments from baseline to after return of results) and sequencing outcomes that reflected participants' perceived understanding of the study and sequencing, regret for joining the study, and responses to learning sequencing results. It also investigated differences in genomic knowledge associated with subgroups differing in race/ethnicity, income, education, health literacy, English proficiency, and prior genetic testing. RESULTS: Multivariate models revealed higher genomic knowledge at baseline for non-Hispanic Whites and those with higher income, education, and health literacy (p values < 0.001). These subgroup differences persisted across study assessments despite a general increase in knowledge among all groups. Greater baseline genomic knowledge was associated with lower test-related distress (p = 0.047) and greater perceived understanding of diagnostic genomic sequencing (p values 0.04 to <0.001). CONCLUSION: Findings extend understanding of the role of genomic knowledge in psychological outcomes of diagnostic exome sequencing, providing guidance for additional research and interventions.