Adult Patients With Undiagnosed Conditions and Their Responses to Clinically Uncertain Results From Exome Sequencing

Patients pursuing exome sequencing in their quest for diagnosis will most often receive a
clinically uncertain result. A clinically uncertain result is a result that has some level of
objective uncertainty frequently viewed by clinicians in regard to a patient s diagnosis. A
clinically uncertain result can be a result that is negative, with no reportable variants, or
that includes one or more variants deemed uncertain with regard to the cause of a patient s
illness. Clinically uncertain results present challenges to both providers and patients in
the forms of disclosing and processing uncertain health information. This exploratory study
aims to seek insight into the psychological and behavioral impact of receiving clinically
uncertain results from exome sequencing. Semi-structured phone interviews will be conducted
with approximately 30-40 adult patients with undiagnosed conditions who have received
clinically uncertain result from exome sequencing. The interviews will focus on the
experience of receiving the clinically uncertain result, with emphasis on appraisal of
uncertainty, coping, and other affective and behavioral responses. Interviews will be
transcribed and subjected to thematic analysis. Understanding how patients with undiagnosed
conditions respond to clinically uncertain results from exome sequencing may inform providers
practices around informed consent for exome sequencing and the disclosure of clinically
uncertain results through a greater consideration of patient concerns and challenges with
adaptation. This study may also identify implications for interventions to reduce negative
effects of receiving uncertain genomic information.

- INCLUSION CRITERIA:

- Had endured a diagnostic odyssey of at least 6 months before receiving exome
sequencing. A diagnostic odyssey may be defined as:

- Having a set of clinical symptoms but no diagnosis OR

- Having a clinical diagnosis of a broad category of disease (i.e. ataxia, muscular
dystrophy) but no specific diagnosis OR

- Having a clinical diagnosis composed of psychosomatic and/or descriptive
diagnoses that individually define single symptoms or groups of symptoms (i.e.
migraines, IBS, joint pain), but that do not explain the entire phenotype

- and Had exome sequencing in an attempt to attain diagnosis

- and Received post-test counseling for exome sequencing by a genetic counselor

- and Received a clinically uncertain result from exome sequencing. For the purposes of
this study, a clinically uncertain result is defined as one of the following options:

- One or more VUSs

- A negative test result (no reported variants)

- and Result disclosure for exome sequencing occurred anywhere from 1 week to 7 years
prior to being interviewed

EXCLUSION CRITERIA:

- Exome sequencing results provided a genetic diagnosis for the patient that does not
fall into one of the above inclusion categories

- Patient was under age 18 at time of clinically uncertain result disclosure

- Patient has a cognitive disability that prevents him/her from comprehensibly answering
interview questions

- Patient cannot speak or understand English

Patients who have since received a genetic diagnosis (from some other mechanism besides
their exome sequencing test) may still participate in the study if they are able to recount
their experiences around receiving this sort of exome sequencing result during the time
they were undiagnosed.