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

National Institutes of Health (NIH) logo

National Institutes of Health (NIH)




Undiagnosed Disease

Study type


Funder types




Details and patient eligibility


Background: People with conditions that are unknown or hard to diagnose may be helped by a genetic technique. It is called exome sequencing. It helps diagnose disease by unlocking all the data in a person s genetic code. But the results from it are often unclear. Uncertain results can pose problems for doctors and patients. Researchers want to learn more about how people respond when they get uncertain results. Objective: To study the psychological and behavioral effects of getting uncertain results from exome sequencing. Eligibility: Adults who have: Had a diagnostic odyssey for at least 6 months. An example is having clinical symptoms but no diagnosis. And had exome sequencing to try to reach a diagnosis. Design: Participants will choose a date and time for their interview. They will sign a form to give consent and authorization. Participants will fill out 2 forms. One is the Intolerance of Uncertainty Short Form Scale. The other is the Perceptions of Uncertainties in Genome Sequencing Scale. Both scales ask about what it is like to get clinically uncertain results from exome sequencing. They focus on coping and other behavioral responses. Participants will have a phone interview. It will last for 45-60 minutes. It will be recorded and transcribed. At the start of the call, the researcher will review the consent form with the participant. Participants will give data such as race, education, income, and how long they have been looking for a diagnosis. Participants will read their responses to the 2 scales during the interview.

Full description

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.


26 patients




18 to 100 years old


No Healthy Volunteers

Inclusion and exclusion 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


  • 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.

Trial design

26 participants in 2 patient groups

Adult patients with undiagnosed conditions who have received an uninformative negative result from exome sequence.
Adult patients with undiagnosed conditions who have received one or more variants ofuncertain significance from exome sequence.

Trial contacts and locations



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