Leila Jamal

Introduction: After a patient receives genetic test results that indicate an actionable health condition, cascade genetic screening (CGS) is the process of evaluating the patient's relatives for a potentially elevated genetic risk of disease. The United States primarily relies on patients to communicate with their relatives, resulting in suboptimal rates of risk communication, familial genetic testing uptake, and risk-reducing interventions. There is ongoing debate about whether and how best to inform relatives of a potentially increased genetic risk. Methods: We conducted a nationally representative survey of US adults to assess attitudes toward informing at-risk relatives, acceptability of system-mediated communication, and preferences for the patient's role in risk communication. Results: Respondents (n = 2056) overwhelmingly supported informing relatives about their genetic risk across condition types, with minimal disagreement (45% agreed; >30% strongly agreed) they would want to decide for themselves whether their results are shared, though many favorably viewed doctor-supported communication. Direct clinician contact was acceptable (37.4%) or totally acceptable (11.5%) with patient permission but rarely acceptable without consent. Conclusion: Findings indicate strong public support for sharing genetic risk information within families, alongside clear expectations for patient consent, to guide CGS implementation in the United States.

Reproductive decision‐making is a complex process, especially for carriers of a pathogenic X‐linked genetic variant. Studies of X‐linked carriers have identified various personal values and concerns that influence reproductive decisions, but these studies provide limited insight into decisional conflict during the reproductive decision‐making process. This study aims to explore how carriers of variants known to cause Barth syndrome, a rare X‐linked disorder, navigate and experience decisional conflict during reproductive decision‐making. Semi‐structured interviews were conducted with 27 Barth syndrome carriers recruited through the Barth Syndrome Foundation. Data was analyzed using reflexive thematic analysis with special attention paid to narratives of high and low decisional conflict and the values around which decisional conflict occurred. Findings showed that decisional conflict was a result of internal conflicts between competing value systems. To address decisional conflict, carriers re‐prioritized their values, reconsidered the extent to which they allowed certain values to influence reproductive decisions, and altered the content of their values. Value systems could also be reshaped over time by personal experiences, which then could modify levels of decisional conflict in reproductive decisions. Decisional conflict often induces feelings of stress and guilt and could be exacerbated by the opinions of others. Genetic counselors are well equipped to provide decisional and emotional support to X‐linked carriers during reproductive decision‐making, and their services may help reduce decisional conflict and the negative emotions that accompany it. Counselors whose practice involves creating long‐term relationships with patients should help carriers to identify factors that are contributing to internal value conflict and to decide whether and how they want support in this. This support may be provided through long‐term genetic counseling structures or partnerships between genetic counselors, support organizations, and mental health professionals.

BACKGROUND: No disease-specific therapy currently exists for arrhythmogenic right ventricular cardiomyopathy (ARVC), a progressive cardiogenetic condition conferring elevated risk for ventricular arrhythmias, heart failure, and sudden cardiac death. Emerging gene therapies have the potential to fill this gap. However, little is known about how adults with ARVC, or any other inherited cardiomyopathy or arrhythmia syndrome, appraise the risks and benefits of gene therapy research and which considerations may influence their decisions about clinical trial participation. METHODS: Twenty adults with clinically diagnosed and gene-positive ARVC participated in semi-structured interviews that explored perceptions of gene therapy and hypothetical decision-making for gene therapy clinical trial participation. Interview transcripts were qualitatively coded and analyzed. RESULTS: Participants expressed enthusiasm for gene therapy with varied levels of personal interest in trial participation. Although clinical severity appeared to be associated with an elevated interest in early trial participation, participants anticipated weighing both personal and trial-specific factors including life stage, trial stage, risks, benefits, participation burden, study leadership, and anticipated cost of future gene therapy. Adaptation to living with ARVC and involvement in the ARVC patient community were also relevant to decision-making about trial participation. Potential ethical concerns included unquestioning trust in clinical teams collaborating on industry-led trials and vulnerability of those recently diagnosed or with high perceived severity of ARVC symptoms. CONCLUSIONS: Several characteristics of the individual and trial warrant consideration during the informed consent process. Insights from this study may affect trial planning and communication with participants who have inherited cardiac conditions.

Background: Though genomic science has rapidly advanced, efforts to demonstrate the population-level utility of genomics have been slow to follow. It has long been argued that the family is an important unit of significance in genomics, yet it has been challenging to address this in clinical care. This is apparent in how hospital administrators and clinicians in the United States typically approach cascade screening, the process of notifying and offering genetic testing to at-risk relatives of a patient with a hereditary condition. The most common notification approach is proband-led contact, in which the index patient is responsible for communicating a health risk to their relatives. This model has been associated with suboptimal outcomes. In contrast, recent research has shown that system-led contact, in which healthcare or public health institutions initiate communication to relatives with the proband’s consent, has been associated with increased clinical utility and acceptability. Summary: With the needs of hospital administrators and clinicians in mind, we revisit normative questions about the appropriate way to notify relatives about their potentially elevated risk of developing an actionable disease. We review evidence demonstrating that system-led direct contact of relatives is feasible and acceptable. We further argue that system-led contact of relatives eligible for cascade screening is ethically justified if these programs are designed with public input, have an opt-out provision, and are implemented for conditions that meet specific criteria which we propose in this article. Key Messages: In this article, we emphasize the usefulness of public health ethics frameworks to inform the design of system-led contact programs. Beyond this, we make the case that such programs are necessary to realize the population utility of genomic medicine equitably.

Transgender and gender diverse (TGD) individuals are a significant yet underrepresented population within genetic counseling research and broader LGBTQI+ health studies. This underrepresentation perpetuates a cycle of exclusion from the production of medical knowledge, impacting the quality and equity of care received by TGD individuals. This issue is particularly poignant in cancer genetic counseling, where TGD individuals with elevated cancer risk receive risk assessment, counseling, and referral to support based on risk figures and standards of care developed for cisgender individuals. The experiences of TGD individuals navigating inherited cancer syndromes remain largely undocumented in medical literature, posing challenges to the provision of inclusive care by genetics providers. To bridge this knowledge gap, we conducted a cross‐sectional qualitative study. Nineteen semi‐structured interviews were held with gender diverse adults having hereditary cancer syndromes, family histories of such syndromes, or personal histories of chest cancer. Our study employed thematic analysis using combined inductive and deductive methods to illuminate how hereditary cancer care intersects with participants' gender identities, gender expression, and gender‐affirming care experiences. Participants reflected on care experiences that felt affirming or triggered gender dysphoria. Participants also discussed the interplay between risk‐reducing mastectomy and top surgery, exploring co‐emergent dynamics between cancer risk management and gender expression. Significantly, participants identified actionable strategies for healthcare providers to enhance support for gender diverse patients, including the mindful use of gendered language, collaborative decision‐making, and conveying allyship. These findings offer valuable insights into tailoring genetic counseling to meet the unique needs of TGD individuals, advancing the path toward inclusive and appropriate care for LGBTQI+ individuals with hereditary cancer syndromes.

Background: Limiting high-intensity exercise is recommended for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) due to its association with penetrance, arrhythmias, and structural progression. Guidelines recommend shared decision-making (SDM) for exercise level, but there is little evidence regarding its impact. Therefore, we sought to evaluate the extent and implications of SDM for exercise, decisional conflict, and decisional regret in patients with ARVC and at-risk relatives. Methods: Adults diagnosed with ARVC or with positive genetic testing enrolled in the Johns Hopkins ARVC Registry were invited to complete a questionnaire that included exercise history and current exercise, SDM (SDM-Q-9), decisional conflict, and decisional regret. Results: The response rate was 64.8%. Two-thirds of participants (68.0%, n=121) reported clinically significant decisional conflict regarding exercise at diagnosis/genetic testing (DCS [decisional conflict scale]≥25), and half (55.1%, n=98) in the past year. Prevalence of decisional regret was also high with 55.3% (n=99) reporting moderate to severe decisional regret (DRS [decisional regret scale]≥25). The extent of SDM was highly variable ranging from no (0) to perfect (100) SDM (mean, 59.6±25.0). Those diagnosed in adolescence (≤age 21) reported significantly more SDM ( P =0.013). Importantly, SDM was associated with less decisional conflict (ß=−0.66, R ² =0.567, P 2 =0.180, P P =0.56; P =0.34, respectively). Conclusions: SDM is associated with lower decisional conflict and decisional regret; and no difference in postdiagnosis exercise. Our data thus support SDM as the preferred model for exercise discussions for ARVC.

The majority of genomic sequencing and microarray results are clinically uninformative, meaning that they do not suggest a need for any behavioral action or medical intervention. Prior studies have shown that recipients of uninformative genomic testing results ("uninformative results" hereafter) may incorrectly interpret them to imply a lowered risk of disease or false reassurance about future health risks. Few studies have examined how patients understand uninformative results when they are returned in a research setting, where there is wide variation in analytical specifications of testing, interpretation and reporting practices, and resources to support the return of results. We conducted cross-sectional interviews (N = 17) to explore how a subset of research participants in one genomics study at the National Institutes of Health reacted to and understood their uninformative test results, which were returned to them via a patient portal without genetic counseling. We found that most participants did not remember the details of the informed consent process, including the distinction between "primary" and "secondary" findings. Participants had questions about what genes were tested for and, in most cases, requested a list of the genes covered. Several participants incorrectly assumed that autosomal recessive carrier results would have been reported to them if detected. Some participants interpreted their uninformative results to mean that they could forgo prenatal testing, and participants had mixed expectations about whether their results might be reinterpreted in the future. These themes suggest that there are specific challenges to returning uninformative results in research settings. Educational supplements to uninformative test reports may be most useful if they contextualize results in relation to other types of clinical genetic or genomic testing that may be made available to research participants in their lifetimes.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphadenopathy, splenomegaly, cytopenias, and other autoimmune manifestations. ALPS is caused by lymphocyte accumulation from defects in FAS-mediated apoptosis. Heterozygous germline or somatic pathogenic single nucleotide variants in FAS are the most common molecular etiology of ALPS. Through the Centralized Sequencing Program at the National Institute of Allergy and Infectious Diseases, we performed exome sequencing on subjects with a clinical diagnosis of ALPS, with a subset receiving copy number variant (CNV) analysis. In this cohort, we identified 3 subjects from unrelated families with CNVs at the FAS locus. One subject had a de novo ∼0.828 Mb copy number loss encompassing all of FAS. The second subject had a maternally inherited ∼1.004 Mb copy number loss encompassing all of FAS. The third subject had a paternally inherited ∼0.044 Mb copy number loss encompassing exons 7 through 9 of FAS. Subjects with deletions in FAS had clinical presentations and biomarker profiles similar to those with ALPS and with germline and somatic FAS variants. We demonstrate that CNV analysis should be pursued if there is clinical and biomarker evidence of ALPS because it can lead to a molecular diagnosis and appropriate treatment when FAS sequencing is inconclusive.

Background: During the COVID-19 pandemic, frontline workers faced a series of challenges balancing family and work responsibilities. These challenges included making decisions about how to reduce COVID-19 exposure to their families while still carrying out their employment duties and caring for their children. We sought to understand how frontline workers made these decisions and how these decisions impacted their experiences. Methods: Between October 2020 and May 2021, we conducted 61 semi-structured interviews in English or Spanish, with individuals who continued to work outside of the home during the pandemic and had children living at home. Interviews were recorded, transcribed verbatim, and analyzed using abductive methods. Results: Frontline workers experienced moral distress, the inability to act in accordance with their values and obligations because of internal or external constraints. Their moral distress was a result of the tensions they felt as workers and parents, which sometimes led them to feel like they had to compromise on either or both responsibilities. Individuals felt morally conflicted because 1) their COVID-19 work exposures presented risk that often jeopardized their family’s health; 2) their work hours often conflicted with their increased childcare responsibilities; and 3) they felt a duty to their colleagues, patients/customers, and communities to continue to show-up to work. Conclusions: Our findings point to a need to expand the concept of moral distress to include the perspectives of frontline workers outside of the healthcare professions and the fraught decisions that workers make outside of work that may impact their moral distress. Expanding the concept of moral distress also allows for a justice-based framing that can focus attention on the disparities inherent in much frontline work and can justify programmatic recommendations, like increasing paid childcare opportunities, to alleviate moral distress.