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

Abstract

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. Semistructured 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.

The diagnostic odyssey: insights from parents of children living with an undiagnosed condition

“…A requirement to make sense for our parents, and those in other studies [ 33 ], is often needed from the moment health care concerns are raised about their child. While our parents convey a degree of “acclimation to illness uncertainty” [ 15 p7] that many people living with undiagnosed diseases develop, managing the uncertainty eating us up remains a significant issue. Compounding this is the need to rattle cages , to meet not only day to day care, but the diagnostic needs of their children, in some cases causing burnout .…”

“…Despite studies exploring MUS and the growing body of literature making reference to a diagnostic odyssey for people living with rare diseases, there is a lack of literature that captures the detail of the lived experience of these journeys from the patient and carer perspective. A number of qualitative studies have addressed this in part through a focus on the outcomes of diagnostic (often genetic) investigations for rare diseases in both adults [ 15 ] and children [ 9 , 16 ]. However, until recently, there has been limited literature addressing the experiences of parents of children with undiagnosed conditions, especially with respect to their diagnostic odyssey journey before the outcome of an investigative process is received, and their orientation towards this outcome.…”

Genetic counseling and testing for hereditary hemorrhagic telangiectasia

“…As sequence variants are often deemed to be of uncertain significance, patients pursuing genetic testing may experience unresolved uncertainty or unease from their sequencing results. 61 Clinicians and genetic counselors should therefore be aware of patients' concerns and challenges with adjusting to such uncertainty and should attempt to identify familial pathogenic variants in affected relatives prior to performing genetic testing on at-risk individuals in order to decrease the likelihood of an uncertain diagnosis.…”