Investigating the Feasibility and Implementation of Whole Genome Sequencing in Patients With Suspected Genetic Disorder

The goal of this research protocol is to conduct a randomized clinical trial to assess the benefits and risks of incorporating whole genome sequencing (WGS) as a first line diagnostic test in various genetic and sub-specialty clinics within a large, tertiary medical center.

The investigators will enroll 500 participants within the Partners HealthCare system (e.g. Massachusetts General Hospital, Massachusetts Eye and Ear, etc.). The study will be enrolling from multiple genetics and sub-specialty clinics, including but not limited to: cardiology, GI cancer genetics, medical genetics, ataxia, endocrine genetics. Participants are eligible if their provider orders genetic testing for diagnosis of symptoms suspicious for a genetic disorder. Participants must not have had a genetic workup in the past.

At the time of enrollment, a small blood sample will be obtained at the time of the participant's blood draw for standard-of-care testing. All participants will be subject to 1:1 randomization, in which 250 will receive a WGS report, and 250 will be randomized to the arm that receives standard of care testing only. Any WGS report that is generated will be incorporated into the patient's electronic medical record.

For pediatric patients, the study team will attempt to collect blood samples from both biological parents when possible for trio analysis (WGS performed on the proband and both biological parents). The purpose of trio analysis is primarily for the purpose of interpreting the proband/child's results. For non-pediatric patients, saliva samples may be requested from living parents for confirmation purposes. No genetic testing reports will be generated for parents. The exception to this is if a parent of a pediatric patient (part of trio) opts to receive results from the ACMG 59 list.

The participants are blinded to the arm in which they are assigned until 3-4 months from the time of consent. At that time, a study genetic counselor will call the participant to disclose the randomization assignment. If the participant was randomized to receive a WGS report, a plan will be made to review the WGS either by phone, video conferencing, or in person. After reviewing the results, the research team will write a letter to the participant summarizing the results and any relevant medical management recommendations. This letter will also include a copy of their WGS report.

All participants (or their parents) will be surveyed at three points during their enrollment: baseline (at time of consent), immediately post-disclosure, and 6 months post-disclosure. The medical providers who offered the standard of care testing will also be surveyed.

Inclusion criteria

• Participants of any gender over the age of 3 months.
• Participants (ages 7+) must be proficient in English. If the participant is under the age of 7 or is over the age of 7 and non-verbal, these criteria apply to their parent who is providing consent.
• Participant is being evaluated clinically at an Partners HealthCare genetics clinic, and not had a prior genetic work up for their referral indication.
• Have a suspected genetic disorder in which the genetic cause is unknown, as confirmed by review of the subject's medical records.
• Genetic testing has been ordered for the participant by their clinical genetics provider as part of a diagnostic workup.
• Willing and able to provide a blood sample. The amount of blood drawn from a patient will be 2 teaspoons or less.
• Ability to provide informed consent or assent to participate in this protocol. Children who have not attained the legal age of consent must provide assent (those who do not have the capacity to assent must not object to taking part), along with permission from the child's parent(s) or guardian. Adults who are unable to consent must be able to provide assent or must not object to taking part, along with permission from their legal authorized representative (LAR).

Exclusion criteria

• Participants who live outside of the United States.
• Non-English-speaking participants.