Working… Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03829176
Recruitment Status : Completed
First Posted : February 4, 2019
Last Update Posted : November 18, 2020
Broad Institute
Laboratory for Molecular Medicine
Information provided by (Responsible Party):
Sekar Kathiresan, Massachusetts General Hospital

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Hereditary Disease Genetic Predisposition to Disease Genetic: Whole Genome Sequencing Not Applicable

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Masking Description: Participant, care provider, and study genetic counselor will be blinded to the arm in which the participant was assigned until 3-4 months post-enrollment when the laboratory notifies if a WGS report is generated or not.
Primary Purpose: Diagnostic
Official Title: Investigating the Feasibility and Implementation of Whole Genome Sequencing in Patients With Suspected Genetic Disorder
Actual Study Start Date : March 1, 2018
Actual Primary Completion Date : October 1, 2020
Actual Study Completion Date : October 1, 2020

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.

Primary Outcome Measures :
  1. 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

  2. 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

Secondary Outcome Measures :
  1. 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.

  2. Participant characteristics [ Time Frame: Baseline ]
    Age, sociodemographics, personal and family history

  3. 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

  4. Physician confidence and attitudes about genomic sequencing [ Time Frame: Baseline ]
    Assessed in physician surveys

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   3 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03829176

Layout table for location information
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Broad Institute
Laboratory for Molecular Medicine
Layout table for investigator information
Principal Investigator: Sekar Kathiresan, MD Massachusetts General Hospital
Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Németh AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sørensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015 Jul;47(7):717-726. doi: 10.1038/ng.3304. Epub 2015 May 18.
Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, Nalpathamkalam T, Pellecchia G, Yuen RKC, Szego MJ, Hayeems RZ, Shaul RZ, Brudno M, Girdea M, Frey B, Alipanahi B, Ahmed S, Babul-Hirji R, Porras RB, Carter MT, Chad L, Chaudhry A, Chitayat D, Doust SJ, Cytrynbaum C, Dupuis L, Ejaz R, Fishman L, Guerin A, Hashemi B, Helal M, Hewson S, Inbar-Feigenberg M, Kannu P, Karp N, Kim R, Kronick J, Liston E, MacDonald H, Mercimek-Mahmutoglu S, Mendoza-Londono R, Nasr E, Nimmo G, Parkinson N, Quercia N, Raiman J, Roifman M, Schulze A, Shugar A, Shuman C, Sinajon P, Siriwardena K, Weksberg R, Yoon G, Carew C, Erickson R, Leach RA, Klein R, Ray PN, Meyn MS, Scherer SW, Cohn RD, Marshall CR. Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine. NPJ Genom Med. 2016 Jan 13;1. pii: 15012. doi: 10.1038/npjgenmed.2015.12.
RARE Diseases: Facts and Statistics. (2017, March 29). Retrieved July 19, 2017, from

Layout table for additonal information
Responsible Party: Sekar Kathiresan, Director of the Center for Genomic Medicine, Massachusetts General Hospital Identifier: NCT03829176    
Other Study ID Numbers: 2017P001832
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: November 18, 2020
Last Verified: November 2020

Layout table for additional information
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
Keywords provided by Sekar Kathiresan, Massachusetts General Hospital:
Whole Genome Sequencing
Additional relevant MeSH terms:
Layout table for MeSH terms
Genetic Diseases, Inborn
Disease Susceptibility
Genetic Predisposition to Disease
Disease Attributes
Pathologic Processes