NCGENES: North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing (NCGENES)

This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. This sub-project is investigating benefits and harms of providing WES diagnostic and different types of incidental findings to adult patients and parents of pediatric patients who undergo WES because they have symptoms suggesting genetic disease.

This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. Participants are patients who were either seen in the University of North Carolina Cancer and Adult Genetics Clinic or referred to the study by their physician. They will be approached by their physician or a genetic counselor for recruitment. Once enrolled, a clinical geneticist or genetic counselor will obtain consent and collect blood samples to be analyzed using WES. Results may include information related to a diagnosis and incidental information. Medically actionable incidental findings will be CLIA (Clinical Laboratory Improvement Amendments)-certified and returned to participants in a routine genetic counseling session, along with diagnostic findings. Eligible adult participants will be randomized to have the opportunity to choose to get certain types of non-medically actionable incidental findings, as well. Their decisions will be investigated, as will psychosocial and behavioral responses to sequencing and receiving sequencing information. This is a longitudinal, mixed methods study (i.e., multiple assessments pre- and post-return of results, with both quantitative and qualitative methods used to gather data). Because only the quantitative component of the study uses randomization, only measures and procedures associated with that component are described here.

Cancer, Cardiovascular disease, Neurodegenerative disease, Neurodevelopmental disease, Dysmorphology, Hearing loss, Other conditions, including ophthalmic conditions

Option to request non-medically actionable incidental information (after receiving education about them)

Option to request non-medically actionable incidental information (after receiving education about them)

2 weeks after return of diagnostic results; for adult patient participants who are eligible and who request them, 2 weeks after return of non-medically actionable incidental results

Adult patient participants: change from 2 weeks after return of diagnostic results to 3 months and 6 months after return of diagnostic results

Participants will answer questions about the extent to which they sought information about whole exome sequencing and results it produces. Questions also ask about sources of that information (e.g., the Internet, doctors) to provide descriptive data about how participants get information.

Also administered 2 wks after return of non-medically actionable incidental results for eligible adult patient participants who request them.

All participants: 2 wks after return of diagnostic (dx) results and, for eligible adults who request them, return of incidental results

For all participants: Change from post-consent to post-return of results; Additional for adults: change at 3 and 6 months after return of dx results

All participants: Change in utilization from post-consent to post-return of results; Additional for adult patients: Change at 3 and 6 months after return of dx results

Adult participants: Change in behaviors from 2 wks after consent (T1) to 2 wks, 3 months, and 6 months after return of dx results

All participants: Change from 2 wks after consent (T1) to 2 wks after return of diagnostic (dx) results; Additional for adult patients: Change at 3 and 6 months after return of dx results

- To receive whole exome sequencing in the study, adult or child patients must have a significant chance of having a genetic disorder, as determined by experts on the study team using criteria that depend on the genetic disorder in question. Representative criteria are listed below and will be considered together to determine whether patterns indicate a likely genetic etiology. Cancer Age of diagnosis Presence of bilateral (or multiple) cancers Diagnosis of a rare type of cancer Details of the family history Cardiovascular Conditions Certain clinical findings, such as prolonged QT interval on electrocardiogram. Presence of hypertrophic cardiomyopathy or aortic aneurysm Age of diagnosis Presence of family history Pediatric neurodevelopmental disorders Specific brain structural brain abnormalities Presence of certain seizure types Dysmorphic features

Raw genotype calls from whole exome sequencing are shared with the database of Genotypes and Phenotypes (dbGaP). Other participant demographic variables include: age of onset, birthplace, sex, race, education level, age. Data is uploaded in batches to the dbGaP website. Currently, the data for 403 participants who have consented for release of their data is available on the dbGaP website. To access data, users must request authorized access by submitting a Data Use Agreement certified by their institution. This is reviewed by the DbGaP Data Access Committee for approval prior to accessing study data. All data that is submitted to dbGaP, including individual participant data, is anonymous.

Rini C, Roche MI, Lin FC, Foreman AKM, Khan CM, Griesemer I, Waltz M, Lee K, O'Daniel JM, Evans JP, Berg JS, Henderson GE. Burden or benefit? Effects of providing education about and the option to request additional genomic findings from diagnostic exome sequencing: A randomized controlled trial. Patient Educ Couns. 2021 Dec;104(12):2989-2998. doi: 10.1016/j.pec.2021.04.026. Epub 2021 Apr 29.