Beyond Utility: Rethinking the value of genetic diagnosis in pediatric rare disease

Meghan Halley – Stanford Center for Bioethics

Abstract: The expansion of genome-wide sequencing (GWS, including exome and genome sequencing) has generated justifiable excitement among patients, families, and providers seeking explanations for undiagnosed, rare genetic conditions. Though the lack of therapies for rare diseases continues to limit the impact diagnosis can have on patient outcomes, research now suggests that patients, families, and providers may derive significant value from diagnosis in the form of connection to social support groups, insights to guide clinical and reproductive decision-making, and other forms of personal and clinical utility. Studies attempting to empirically evaluate outcomes beyond diagnostic utility continue to suffer from significant methodological limitations, including a lack of conceptual clarity, standardized measures, and long-term outcomes data. To address these gaps, we conducted a two-year prospective ethnography with 36 parents of children receiving GWS to diagnose a suspected rare disease. Participants were interviewed at three time points to understand their perspectives on the expected utility of sequencing and the benefits experienced over time. Our results focus on three themes: 1) the reported value derived from sequencing was shaped by multiple individual, family, and contextual factors, as well as by specific diagnostic characteristics; 2) families without a definitive diagnosis reported achieving similar benefits through alternative means, notably improved clinical care coordination; and 3) value of GWS evolved dynamically, with both benefits and harms diminishing over time. Our results suggest that the extant literature on the utility of GWS does not reflect families' multi-dimensional and dynamic perspectives regarding the value of this technology for diagnosing rare diseases.

Keywords: ELSI, Rare disease, Utility