Adult patients with undiagnosed conditions and their responses to unresolved uncertainty from exome sequencing

Patients pursuing exome sequencing (ES) in their quest for diagnosis will most often experience unresolved uncertainty from their ES results because the majority of ES results are non-diagnostic. This study explored and compared the experiences of receiving two types of ES results that may result in diagnostic uncertainty. Semi-structured phone interviews were conducted with 23 adult patients with undiagnosed conditions who received either a negative result or a result with one or more variants of uncertain significance (VUSs) from ES. Interviews were transcribed and subjected to thematic and comparative analyses. Participants accurately understood their results and described various sources of genomic uncertainty including probability, complexity, and ambiguity. Their acclimation to illness uncertainty resulted in realistic expectations about and acceptance of their results. Participants still hoped that ES would end their diagnostic odyssey. Hope and optimism were used to cope with continued uncertainty. No thematic differences were found between the experiences of those who received negative results versus those who received VUSs. Our findings may inform clinical practices of informed consent and disclosure of negative results and VUSs through a greater consideration of patients' reactions, concerns, and challenges with adaptation to uncertainty.