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.

- 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.