2021 McKusick Leadership Award: Learning from communities.

This article is based on the address given by the author at the 2021 virtual meeting of the American Society of Human Genetics (ASHG). The video of the original address can be found at the ASHG website.

Is there a way to reduce the inequity in variant interpretation on the basis of ancestry?

The underrepresentation of non-European ancestry groups in current genomic databases complicates interpretation of their genetic test results, yielding a much higher prevalence of variants of uncertain significance (VUSs). Such VUS findings can frustrate the goals of genetic testing, create anxiety in patients, and lead to unnecessary medical interventions. Approaches to addressing underrepresentation of people with genetic ancestries other than European are being undertaken by broad-based recruitment efforts. However, some underrepresented groups have concerns that might preclude participation in such efforts. We describe here two initiatives aimed at meeting the needs of underrepresented ancestry groups in genomic datasets. The two communities, the Sephardi Jewish community in New York and First Peoples of Canada, have very different concerns about contributing to genomic research and datasets. Sephardi concerns focus on the possible negative effects of genetic findings on the marriage prospects of family members. Canadian Indigenous populations seek control over the research uses to which their genetic data would be put. Both cases involve targeted efforts to respond to the groups' concerns; these efforts include governance models aimed at ensuring that the data are used primarily to inform clinical test analyses and at achieving successful engagement and participation of community members. We suggest that these initiatives could provide models for other ancestral groups seeking to improve the accuracy and utility of clinical genetic testing while respecting the underlying preferences and values of community members with regard to the use of their genetic data.

Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial.

BACKGROUND: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. METHODS: The DCM Precision Medicine Study developed Family Heart Talk, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. RESULTS: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (P=0.90). CONCLUSIONS: Family Heart Talk, a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

Utility and Diversity: Challenges for Genomic Medicine.

Genomic information is poised to play an increasing role in clinical care, extending beyond highly penetrant genetic conditions to less penetrant genotypes and common disorders. But with this shift, the question of clinical utility becomes a major challenge. A collaborative effort is necessary to determine the information needed to evaluate different uses of genomic information and then acquire that information. Another challenge must also be addressed if that process is to provide equitable benefits: the lack of diversity of genomic data. Current genomic knowledge comes primarily from populations of European descent, which poses the risk that most of the human population will be shortchanged when health benefits of genomics emerge. These two challenges have defined my career as a geneticist and have taught me that solutions must start with dialogue across disciplinary and social divides.

Genetic research within Indigenous communities: Engagement opportunities and pathways forward.

PURPOSE: Against a historical backdrop of researchers who violated trust through lack of benefit sharing, transparency, and engagement, efforts are underway to develop better approaches for genetic and genomic research with Indigenous communities. To increase engagement, there is a need to understand factors that affect researcher and community collaborations. This study aimed to understand the barriers, challenges, and facilitators of Indigenous Peoples in the United States participating in genetic research. METHODS: We conducted 42 semistructured interviews with Tribal leaders, clinicians, researchers, policy makers, and Tribal research review board members across the United States to explore perceived risks, benefits, barriers, and facilitators of genetic research participation. RESULTS: Participants, identifying as Indigenous (88%) or non-Indigenous allies (12%), described their concerns, hesitancy, and fears about genetic research, as well as the roles of trust, transparency, and respect for culture in facilitating partnerships. Previous harms-such as sample and data misuse, stigmatization, or misrepresentation by researchers-revealed strategies for building trust to create more equitable and reciprocal research partnerships. CONCLUSION: Participants in this study offered strategies for increasing genetic research engagement. The pathway forward should foster transparent research policies and practices to facilitate informed research that supports the needs and priorities of participants, communities, and researchers.

Cases in Precision Medicine: Is There an Obligation to Return Reinterpreted Genetic Results to Former Patients?

Interpretation of many genetic test results can change over time as new data accumulate. Hence, physicians who order genetic tests may subsequently receive revised reports with important implications for patients' medical treatment-even for patients who are no longer in their care. Several of the ethical principles underlying medical practice suggest an obligation to reach out to former patients with this information. Discharging that obligation can be accomplished, at a minimum, by attempting to contact the former patient with their last known contact information.

Ethical Considerations in Precision Medicine and Genetic Testing in Internal Medicine Practice: A Position Paper From the American College of Physicians.

This American College of Physicians position paper aims to inform ethical decision making for the integration of precision medicine and genetic testing into clinical care. Although the positions are primarily intended for practicing physicians, they may apply to other health care professionals and can also inform how health care systems, professional schools, and residency programs integrate genomics into educational and clinical settings. Addressing the challenges of precision medicine and genetic testing will guide ethical and responsible implementation to improve health outcomes.

The Challenge of Genetic Variants of Uncertain Clinical Significance : A Narrative Review.

Genomic tests expand diagnostic and screening opportunities but also identify genetic variants of uncertain clinical significance (VUSs). Only a minority of VUSs are likely to prove pathogenic when later reassessed, but resolution of the uncertainty is rarely timely. That uncertainty adds complexity to clinical decision making and can result in harms and costs to patients and the health care system, including the time-consuming analysis required to interpret a VUS and the potential for unnecessary treatment and adverse psychological effects. Current efforts to improve variant interpretation will help reduce the scope of the problem, but the high prevalence of rare and novel variants in the human genome points to VUSs as an ongoing challenge. Additional strategies can help mitigate the potential harms of VUSs, including testing protocols that limit identification or reporting of VUSs, subclassification of VUSs according to the likelihood of pathogenicity, routine family-based evaluation of variants, and enhanced counseling efforts. All involve tradeoffs, and the appropriate balance of measures is likely to vary for different test uses and clinical settings. Cross-specialty deliberation and public input could contribute to systematic and broadly supported policies for managing VUSs.

Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry.

Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

Precision medicine research with American Indian and Alaska Native communities: Results of a deliberative engagement with tribal leaders.

PURPOSE: Amid calls for greater diversity in precision medicine research, the perspectives of Indigenous people have been underexplored. Our goals were to understand tribal leaders' views regarding the potential benefits and risks of such research, explore its priority for their communities, and identify the policies and safeguards they consider essential. This article reports on the participants' perspectives regarding governance and policy, stewardship and sharing of information and biospecimens, and informed consent. METHODS: After informal local dialogs with 21 tribal leaders, we convened a 2.5-day deliberation with tribal leaders (N = 10) in Anchorage, Alaska, in June 2019 using a combination of small group and plenary discussion, ranking, and voting exercises to explore the perspectives on precision medicine research. RESULTS: Tribal sovereignty was central to participants' ideas about precision medicine research. Although views were generally positive, provided that the appropriate controls were in place, some kinds of research were deemed unacceptable, and the collection of certain biospecimens was rejected by some participants. Differences were observed regarding the acceptability of broad consent. CONCLUSION: Tribal leaders in this study were generally supportive of precision medicine research, with the caveat that tribal oversight is essential for the establishment of research repositories and the conduct of research involving Indigenous participants.

Diagnosis, Education, and Care of Patients with APOL1-Associated Nephropathy: A Delphi Consensus and Systematic Review.

BACKGROUND: APOL1 variants contribute to the markedly higher incidence of ESKD in Blacks compared with Whites. Genetic testing for these variants in patients with African ancestry who have nephropathy is uncommon, and no specific treatment or management protocol for APOL1-associated nephropathy currently exists. METHODS: A multidisciplinary, racially diverse group of 14 experts and patient advocates participated in a Delphi consensus process to establish practical guidance for clinicians caring for patients who may have APOL1-associated nephropathy. Consensus group members took part in three anonymous voting rounds to develop consensus statements relating to the following: (1) counseling, genotyping, and diagnosis; (2) disease awareness and education; and (3) a vision for management of APOL1-associated nephropathy in a future when treatment is available. A systematic literature search of the MEDLINE and Embase databases was conducted to identify relevant evidence published from January 1, 2009 to July 14, 2020. RESULTS: The consensus group agreed on 55 consensus statements covering such topics as demographic and clinical factors that suggest a patient has APOL1-associated nephropathy, as well as key considerations for counseling, testing, and diagnosis in current clinical practice. They achieved consensus on the need to increase awareness among key stakeholders of racial health disparities in kidney disease and of APOL1-associated nephropathy and on features of a successful education program to raise awareness among the patient community. The group also highlighted the unmet need for a specific treatment and agreed on best practice for management of these patients should a treatment become available. CONCLUSIONS: A multidisciplinary group of experts and patient advocates defined consensus-based guidance on the care of patients who may have APOL1-associated nephropathy.

Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy.

Importance: Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death. Objective: To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups. Design, Setting, and Participants: A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively. Exposures: The presence of DCM in a proband. Main Outcomes and Measures: Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative. Results: The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]). Conclusions and Relevance: In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives. Trial Registration: ClinicalTrials.gov Identifier: NCT03037632.

Is there a duty to reinterpret genetic data? The ethical dimensions.

The evolving evidence base for the interpretation of variants identified in genetic and genomic testing has presented the genetics community with the challenge of variant reinterpretation. In particular, it is unclear whether an ethical duty of periodic reinterpretation should exist, who should bear that duty, and what its dimensions should be. Based on an analysis of the ethical arguments for and against a duty to reinterpret, we conclude that a duty should be recognized. Most importantly, by virtue of ordering and conducting tests likely to produce data on variants that cannot be definitively interpreted today, the health-care system incurs a duty to reinterpret when more reliable data become available. We identify four elements of the proposed ethical duty: data storage, initiation of reinterpretation, conduct of reinterpretation, and patient recontact, and we identify the parties best situated to implement each component. We also consider the reasonable extent and duration of a duty, and the role of the patient's consent in the process, although we acknowledge that some details regarding procedures and funding still need to be addressed. The likelihood of substantial patient benefit from a systematic approach to reinterpretation suggests the importance for the genetics community to reach consensus on this issue.

Exploring relatives' perceptions of participation, ethics, and communication in a patient-driven study for hereditary cancer variant reclassification.

Effective communication of genetic information within families depends on several factors. Few studies explore intra-familial communication of variant of uncertain significance (VUS) results or active collaboration between family members to classify VUS. Our qualitative study aimed to describe the experiences of individuals asked by family members to participate in the FindMyVariant study, a patient-driven family study which aimed to reclassify a clinically identified familial VUS in a hereditary cancer gene. We collected feedback from 56 individuals from 21 different families through phone interviews and written correspondence, transcribed the interviews, and performed thematic analysis on all text. We describe themes from three main topics: participation, ethical considerations, and study impacts. Participation in the FindMyVariant study, defined as returning a sample for targeted genotyping, was motivated by convenience and a desire to help the family, oneself, and science. Relatives were generally responsive to invitations to participate in FindMyVariant from another family member. Those who declined to participate did so due to concerns about research program confidentiality rather than family dynamics. No major ethical issues arose in response to the patient-driven study structure, and no major changes in stress and anxiety, medical care, or behavior occurred. Participation in patient-driven familial VUS classification studies has a neutral or positive impact on family health communication. While it is important to design studies to minimize familial coercion, intra-familial confidentiality breaches, and misinterpretation of genetic results, these were not major concerns among relatives in this study. Clinicians and laboratories may consider encouraging familial communication about genetic variants using family members as liaisons.

Correction to: Native Hawaiian Views on Biobanking.

The original version of this article unfortunately contained a mistake. The name of "Maile Taualii" is now corrected in the author group of this article.

Perceptions of alcohol misuse among Alaska native health care system stakeholders: A qualitative exploration.

Although alcohol misuse is a priority for health care systems serving Alaska Native and American Indian (ANAI) people, stakeholders' perceptions of misuse are understudied. Patients (n = 34), providers (n = 20), and leaders (n = 16) at a Tribally owned and operated health care system reported that alcohol misuse results from the interaction of factors, including colonization, structural factors, social alienation, social norms about overdrinking introduced at the time of colonizing contact, coping with emotions, and beliefs about ANAI people and alcohol. Childhood exposure to alcohol misuse leads some ANAI people to avoid alcohol altogether, shedding light on the high levels of abstinence observed in ANAI communities.

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

Randomized trial of a web-based survivor intervention on melanoma prevention behaviors of first-degree relatives.

OBJECTIVES: Melanoma can be prevented through reducing sun exposure and detected early by increasing examination of skin for lesions. First-degree relatives of melanoma cases have higher risk than the general population and, therefore, could be targets of behavioral interventions through families. We tested the effects of a family-based web delivered intervention to melanoma families on the melanoma risk reduction behaviors of first-degree relatives of melanoma cases. METHODS: A total of 313 families that included one first-degree relative were recruited to join this randomized trial. All intervention families received access to the Suntalk website developed to promote family communication and behavioral risk reduction among families of melanoma survivors. RESULTS: First degree relatives in the intervention arm significantly increased their yearly performance of both skin self examination and thorough provider examination from baseline to 12-month follow-up while the control FDRs decreased their yearly performance of both of those behaviors (p's = 0.006 and 0.005, respectively). Several sun protection behaviors increased significantly in FDRs in the intervention arm but not the control arm, including wearing a covering on the head (p = 0.005), staying in available shade (p = 0.008), and avoiding sun exposure during peak hours (p = 0.010). Some of these changes were mediated by perceptions of risk and other process variables. CONCLUSIONS: A web-based intervention can reduce risk of melanoma through changes in relevant behaviors among first-degree relatives of melanoma survivors. Future research should identify methods for making this type of intervention accessible to more families and for broadening the reach to other types of cancer families. PRACTICE IMPLICATIONS: This program can be provided to melanoma families to improve their sun protection and screening behaviors, at the point of diagnosis.

Improving recommendations for genomic medicine: building an evolutionary process from clinical practice advisory documents to guidelines.

Genomic sequencing and multigene panel tests are moving rapidly into clinical practice for a range of indications, but the evidence to guide appropriate use is currently limited. Well-crafted advice is needed to reduce unjustified practice variation, minimize risk of error and harm to patients, and encourage best practices. In the absence of definitive evidence, provisional advice can be helpful if it clarifies the potential benefits and risks of different courses of action and identifies the knowledge gaps most important to address in future research. This paper proposes an evolutionary process starting with clinical practice advisory documents (CPADs) and culminating in clinical practice guidelines (CPGs), using two case examples to illustrate the need for this process. When evidence is limited, CPADs can clarify current practice options and identify key knowledge gaps. Added evidence can then support updates to the CPADs over time. Ultimately CPADs can provide the foundation for definitive CPGs as the evidence base matures. This approach addresses an important challenge in genomics and may be applicable to other fields in which technology and practice are outpacing evidence generation.

Practice Implications of Expanded Genetic Testing in Oncology.

Genetic test use in oncology is growing, yet providers' experiences with evolving testing norms and their implications for patient care remain under-explored. In interviews with oncologists and cancer genetics professionals, 22 key informants described the increasing importance of germline results for therapeutic decision-making, preference for ordering tests directly rather than referring, and rapid adoption of cancer gene panels for testing. Implications for informed consent, result interpretation, and patient management were identified. These results suggest concerns raised by the transition of genetic test delivery from cancer genetics professionals to oncologists that must be addressed in practice guidelines and provider training.