Julia E. H. Brown

Recent critique of maternal-fetal therapy trial ethical guidance has highlighted the need to weigh maternal, fetal and societal interests, respectively, while deprioritizing psychosocial reasons for participation. Psychosocial reasons refer to the psychological and social influences on study participants' decisions, and they are often central to considerations about informed consent. However, psychosocial reasons are described as too indirect, subjective, and vague to incorporate into prenatal clinical and regulatory frameworks. This qualitative study examines the perspectives of 11 individuals (eight couples) enrolled in one of two maternal-fetal therapy phase I clinical trials for rare genetic conditions. Interviews revealed that motivations to participate were primarily psychosocial, including: existential concerns given prior bereavement and/or fear of loss; temporal control through taking action as opposed to feeling passive; hope and optimism; and intergenerational and social motivations given one's family experience with disease and desire for social connections. Psychosocial reasons for participating ought to be given more consideration in ethical frameworks for maternal-fetal therapy phase I clinical trials, as well as in the approach to informed consent. It is important for clinical research teams to be especially conscientious to ensure appreciation for participants' reasons for participating that extend beyond typical frameworks of clinical risk/benefit, and to support participants who might harbor optimistic expectations of medical procedures as they transition to postnatal realities.

In utero interventions are transformative in addressing genetic and anatomic conditions during fetal development. Next generation sequencing enables early genetic testing, playing a pivotal role in prenatal decision‐making by supporting risk stratification, precise and timely diagnosis, which directly informs eligibility for fetal surgical and molecular therapies. Early diagnosis benefits both prenatal and postnatal care by guiding prenatal interventions, or selecting cases that might benefit from postnatal preparedness (when early postnatal treatment alters outcomes), and informing counseling (when it significantly influences pregnancy decision‐making) and reproductive planning. The integration of artificial intelligence into prenatal care holds the promise of end‐to‐end solutions that streamline diagnosis, counseling, and access to both standard and experimental in utero interventions. However, significant ethical and social challenges remain, including equity in access to testing and care, incidental findings, variants of uncertain significance, incomplete penetrance and uncertain phenotype prediction of rare variants and disorders. These complexities raise important questions about reproductive autonomy and justice and responsible use of emerging technologies. This review emphasizes the intimate interplay between early genetic testing and in utero interventions, while highlighting the need for equitable, precise, and community‐informed practices in prenatal genomic research and care.

This Viewpoint explores how current ethical challenges of N-of-1 trials for serious neurological diseases could be addressed by integrating current approaches into learning healthcare systems.

This Special Section explores questions of method and positionality attached to moral agency in mental healthcare, which give rise to novel methodological and theoretical approaches to everyday life in the clinical and non-clinical spaces where such ‘care’ occurs. Moral agency is the ability to be perceived as a ‘good enough’ person, which makes possible intimate relationships with others that are needed to thrive in many social contexts (Myers 2015). In this introduction, we draw on Mattingly’s (2014) notion of everyday moral laboratories: an exploratory attention to moral life as innovative method, episteme, and interpersonal collaboration. Exploring the everyday moral laboratories where people struggle to replenish or protect their moral agency and so create meaning and relationships in their lives is a key focus of this Special Section. For interdisciplinary ethnographers working in spaces intended for care, such experimentation yields opportunities to more creatively and proactively inform that care—the everyday, the ordinary, and the extraordinary—that centres on helping our interlocutors replenish moral agency and thrive.

The causal mechanisms and manifestations of psychiatric illness cannot be neatly narrowed down or quantified for diagnosis and treatment. Large-scale genome-wide association studies (GWAS) might renew hope for locating genetic predictors and producing precision medicines, however such hopes can also distract from appreciating social factors and structural injustices that demand more socially inclusive and equitable approaches to mental healthcare. A more comprehensive approach begins with recognizing that there is no one type of contributor to mental illness and its duration that should be prioritized over another. We argue that, if the search for biological specificity is to complement the need to alleviate the social distress that produces mental health inequities, psychiatric genomics must incorporate an intersectional dimension to models of mental illness across research priorities, scientific frameworks, and clinical applications. We outline an intersectional framework that will guide all professionals working in the expanding field of psychiatric genomics to better incorporate issues of social context, racial and cultural diversity, and downstream ethical considerations into their work.

Genetic variants in SLC22A5 , encoding the membrane carnitine transporter OCTN2, cause the rare metabolic disorder Carnitine Transporter Deficiency (CTD). CTD is potentially lethal but actionable if detected early, with confirmatory diagnosis involving sequencing of SLC22A5 . Interpretation of missense variants of uncertain significance (VUSs) is a major challenge. In this study, we sought to characterize the largest set to date ( n = 150) of OCTN2 variants identified in diverse ancestral populations, with the goals of furthering our understanding of the mechanisms leading to OCTN2 loss-of-function (LOF) and creating a protein-specific variant effect prediction model for OCTN2 function. Uptake assays with ¹⁴ C-carnitine revealed that 105 variants (70%) significantly reduced transport of carnitine compared to wild-type OCTN2, and 37 variants (25%) severely reduced function to less than 20%. All ancestral populations harbored LOF variants; 62% of green fluorescent protein (GFP)–tagged variants impaired OCTN2 localization to the plasma membrane of human embryonic kidney (HEK293T) cells, and subcellular localization significantly associated with function, revealing a major LOF mechanism of interest for CTD. With these data, we trained a model to classify variants as functional (>20% function) or LOF (<20% function). Our model outperformed existing state-of-the-art methods as evaluated by multiple performance metrics, with mean area under the receiver operating characteristic curve (AUROC) of 0.895 ± 0.025. In summary, in this study we generated a rich dataset of OCTN2 variant function and localization, revealed important disease-causing mechanisms, and improved upon machine learning–based prediction of OCTN2 variant function to aid in variant interpretation in the diagnosis and treatment of CTD.

Genomic sequencing has been increasingly utilized for prenatal diagnosis in recent years and this trend is likely to continue. However, decision-making for parents in the prenatal period is particularly fraught, and prenatal sequencing would significantly expand the complexity of managing health risk information, reproductive options, and healthcare access. This qualitative study investigates decision-making processes amongst parents who enrolled or declined to enroll in the prenatal arm of the California-based Program in Prenatal and Pediatric Genome Sequencing (P3EGS), a study in the Clinical Sequencing Evidence-Generating Research (CSER) consortium that offered whole exome sequencing for fetal anomalies with a focus on underrepresented groups in genomic research. Drawing on the views of 18 prenatal families who agreed to be interviewed after enrolling (n = 15) or declining to enroll (n = 3) in P3EGS, we observed that the timing of sequencing, coupled with unique considerations around experiences of time during pregnancy and prenatal testing, intersect with structural supports beyond the clinic to produce preferences for and against prenatal sequencing and to contain the threat of unwelcome, uncertain knowledge. Particularly for those without structural supports, finding out consequential information may be more palatable after the birth, when the first stage of the uncertain future has been revealed. Future research should examine the role of temporality in decision-making around prenatal genomic sequencing across diverse population cohorts, in order to observe more precisely the role that structural barriers play in patient preferences.

The two target articles in this issue bring into focus the struggle for governance over biomedical interventions that may offer some families more agency—the capacity to act—in the context of many ...