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

November 17, 2020 updated by: Sekar Kathiresan, Massachusetts General Hospital

The study "Investigating the Feasibility and Implementation of Whole Genome Sequencing in Patients With Suspected Genetic Disorder" is a research study that aims to explore the use of whole genome sequencing as a potential first line genetic test for patients for which a genetic diagnosis is suspected. This is an internally funded research study.

The investigators will enroll 500 participants who are being seen in one of the various genetics clinics within the Partners HealthCare system for a suspected genetic disorder for which standard-of-care genetic testing is ordered. At the time of their standard-of-care genetic testing, an extra blood sample will be collected, and genome sequencing may be performed. Within 3-4 months, patients learn if they received genome sequencing or not, and any results are returned and explained. Investigators are also studying the experiences of both participants and their providers to better understand how to implement genome sequencing into clinical care.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

200

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 months and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Participants of any gender over the age of 3 months.
  2. 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.
  3. Participant is being evaluated clinically at an Partners HealthCare genetics clinic, and not had a prior genetic work up for their referral indication.
  4. Have a suspected genetic disorder in which the genetic cause is unknown, as confirmed by review of the subject's medical records.
  5. Genetic testing has been ordered for the participant by their clinical genetics provider as part of a diagnostic workup.
  6. Willing and able to provide a blood sample. The amount of blood drawn from a patient will be 2 teaspoons or less.
  7. 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:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Standard-of-Care
Participants who are randomized to not have whole genome sequencing performed on their sample. These participants will have standard-of-care genetic testing only (ordered by their clinical provider) and will not receive genetic results as part of this study.
Experimental: Whole Genome Sequencing
Participants who are randomized to have their genome sequenced and receive a whole genome sequencing report. Results disclosure sessions will include a discussion of the whole genome sequencing report, how the results compare to their standard-of-care genetic testing report, and any potential relevant recommendations. Participants in this arm will receive a copy of their whole genome sequencing report accompanied by a summary letter written by a study genetic counselor.
Genetic: Whole Genome Sequencing
Participants in this arm will have their sample analyzed by whole genome sequencing (WGS), and a report will be included in their medical record. Analysis will be phenotype-driven (gene list will be curated based on primary indication for testing and other available medical history information), and may include genes on ACMG 59 list if participant elects for these results. This report will include pathogenic, likely pathogenic, and suspicious VUS results identified in the genes analyzed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Diagnostic capabilities: standard-of-care vs whole genome sequencing diagnostic yield
Time Frame: From date of consent until the date of first documented report, assessed up to 12 months
Assess and compare the overall yields for primary and secondary/incidental findings
From date of consent until the date of first documented report, assessed up to 12 months
Diagnostic capabilities: standard-of-care vs whole genome sequencing time to reach diagnosis
Time Frame: From date of consent until the date of first positive report, assessed up to 12 months
Assess and compare the time that is required to reach a diagnosis by both standard-of-care genetic testing and whole genome sequencing
From date of consent until the date of first positive report, assessed up to 12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Resources Needed to Implement WGS at an Academic Medical Center
Time Frame: Baseline to End of Study, up to 2 years
Assess by recording resources needed to implement WGS at an Academic Medical Center by documenting resources needed for engagement, execution, reporting, and evaluation.
Baseline to End of Study, up to 2 years
Participant characteristics
Time Frame: Baseline
Age, sociodemographics, personal and family history
Baseline
Change in perceived utility of genomic results
Time Frame: Baseline, post-disclosure (approximately 3-4 months after enrollment), 6 months post-disclosure
Assessed in participant (or parent) surveys via questions assessing: reasons for decline, motivations for enrollment, change in expectations, confidence, concerns, preferences for information sharing
Baseline, post-disclosure (approximately 3-4 months after enrollment), 6 months post-disclosure
Physician confidence and attitudes about genomic sequencing
Time Frame: Baseline
Assessed in physician surveys
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Collaborators

Broad Institute
Laboratory for Molecular Medicine

Investigators

  • Principal Investigator: Sekar Kathiresan, MD, Massachusetts General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2018

Primary Completion (Actual)

October 1, 2020

Study Completion (Actual)

October 1, 2020

Study Registration Dates

First Submitted

October 30, 2018

First Submitted That Met QC Criteria

January 31, 2019

First Posted (Actual)

February 4, 2019

Study Record Updates

Last Update Posted (Actual)

November 18, 2020

Last Update Submitted That Met QC Criteria

November 17, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2017P001832

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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