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LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02699190
Recruitment Status : Recruiting
First Posted : March 4, 2016
Last Update Posted : September 9, 2020
Illumina, Inc.
Information provided by (Responsible Party):
Adeline Vanderver, MD, Children's Hospital of Philadelphia

Brief Summary:
Leukodystrophies, and other heritable disorders of the white matter of the brain, were previously resistant to genetic characterization, largely due to the extreme genetic heterogeneity of molecular causes. While recent work has demonstrated that whole genome sequencing (WGS), has the potential to dramatically increase diagnostic efficiency, significant questions remain around the impact on downstream clinical management approaches versus standard diagnostic approaches.

Condition or disease
Leukodystrophy White Matter Disease

Detailed Description:

Leukodystrophies are a group of approximately 30 genetic diseases that primarily affect the white matter of the brain, a complex structure composed of axons sheathed in myelin, a glial cell-derived lipid-rich membrane. Leukodystrophies are frequently characterized by early onset, spasticity and developmental delay, and are degenerative in nature. As a whole, leukodystrophies are relatively common (approximately 1 in 7000 births or almost twice as prevalent as Prader-Willi Syndrome, which has been far more extensively studied) with high associated health-care costs; however, more than half of the suspected leukodystrophies do not have a definitive diagnosis, and are generally classified as "leukodystrophies of unknown etiology". Even when a diagnosis is achieved, the diagnostic process lasts an average of eight years and results in test expenses in excess of $8,000 on average per patient, including the majority of patients who never achieve a diagnosis at all. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients. The diagnostic workup begins with findings on cranial Magnetic Resonance Imaging (MRI) followed by sequential targeted genetic testing, however next generation sequencing technologies (NGS) offer the promise of rapid and more cost effective approaches.

Despite significant advances in diagnostic efficacy, there are still significant issues with respect to implementation of NGS in clinical settings. First, sample cohorts demonstrating diagnostic efficacy are generally small, retrospective, and susceptible to ascertainment bias, ultimately rendering them poor candidates for utility analyses (to determine how efficient a test is at producing a diagnosis). Second, historic sample cohorts have not been examined prospectively for information about impact on clinical management (whether the test results in different clinical monitoring, a change in medications, or alternate clinical interventions).

To address these issues, the study team conducted an investigation of patients with suspected leukodystrophies or other genetic disorders affecting the white matter of the brain at the time of initial confirmation of MRI abnormalities, with prospective collection of patients randomly received on a "first come, first served" basis from a network of expert clinical sites. Subjects were randomized to receive early (1 month) or late (6 months) WGS, with SoC clinical analyses conducted alongside WGS testing. An interim analysis performed in May 2018 assessed these study outcomes for a cohort of thirty-four (34) enrolled subjects. Two of these subjects were resolved before complete enrollment and were retained as controls. Nine subjects were stratified to the Immediate Arm, of which 5 (55.6%) were resolved by WGS and 4 (44.4%) were persistently unresolved. Of the 23 subjects randomized to the Delayed Arm, 14 (60.9%) were resolved by WGS and 5 (21.7%) by SoC, while the remaining 4 (17.4%) remained undiagnosed. The diagnostic efficacy of WGS in both arms was significant relative to SoC (p<0.005). The time to diagnosis was significantly shorter in the immediate WGS group (p<0.05). The overall diagnostic efficacy of the combination of WGS and SoC approaches was 26/34 (76.5%; 95% CI = 58.8% to 89.3%) over <4 months, greater than historical norms of <50% over more than 5 years.

The study now seeks to determine whether WGS results in changes to clinical management in subjects affected by undiagnosed genetic disorders of the white matter of the brain relative to standard diagnostic approaches. We anticipate that WGS will produce measurable downstream changes in clinical management, as defined by disease-specific screening for complications or implementation of disease-specific therapeutic approaches.

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Study Type : Observational
Estimated Enrollment : 450 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
Actual Study Start Date : January 6, 2017
Estimated Primary Completion Date : August 2, 2021
Estimated Study Completion Date : August 2, 2021

Resource links provided by the National Library of Medicine

Prospective Study Cohort
This cohort comprises recently identified individuals for whom a clinical decision has been made to pursue whole genome sequencing (WGS) as a first-line diagnostic test. The cohort also includes each subject's biological parents.
Historical Study Cohort
This cohort comprises approximately 50 historical controls who received either whole genome sequencing (WGS) or standard diagnostic testing as part of their participation in a previous version of this protocol, which used a randomized controlled design to assess diagnostic efficacy of WGS. This cohort is closed to new enrollment, and exists for statistical analysis purposes only.

Primary Outcome Measures :
  1. Changes in Clinical Management (Resulting from WGS) [ Time Frame: 01/06/2017 - 08/26/2019 ]
    The primary objective of this study is to evaluate changes in clinical management between the study cohort, who will undergo whole genome sequencing (WGS) as part of clinical care, and a historical cohort of patients whose diagnoses were established using standard (i.e. non-WGS) diagnostic approaches. Differences in clinical management will be measured at six months following disclosure of results.

Secondary Outcome Measures :
  1. Time to Implementation of Changes in Clinical Management (Resulting from WGS) [ Time Frame: 01/06/2017 - 08/26/2019 ]
    Determine whether time to implementation of clinical management approaches differs between subjects who received whole genome sequencing over standard diagnostic approaches.

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.

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
We expect participants to be identified during their initial presentation and preliminary diagnostic workup. Leukodystrophies are heritable conditions that - with only few exceptions - are not gender-specific. We therefore expect males and females to be equally represented in the study population. The age of presentation is variable ranging from infancy to adulthood, though enrollment for the study is limited to individuals who have not yet reached the age of 18. All ethnicities are equally represented in these disorders, and we expect ethnicities to be represented based on US census data of population distribution.

Inclusion Criteria:

  1. Abnormalities of the white matter signal on neuroimaging (MRI) with T2 hyperintensity which must be diffuse or involve specific anatomical tracts consistent with a genetic diagnosis;
  2. No pre-existing genetic diagnosis;
  3. A clinical decision has been made to perform WGS;
  4. Less than 18 years of age;
  5. Availability of both biologic parents for blood sampling;
  6. Availability both biological parents to provide informed consent;
  7. Concurrently enrolled in CHOP IRB 14-011236 (New Diagnostic Approaches in Leukodystrophy - The Myelin Disorders Biorepository Project)

Exclusion Criteria:

  1. Candidates with acquired disorders, including infection, acute disseminated encephalomyelitis (ADEM), multiple sclerosis, vasculitis or toxic leukoencephalopathies;
  2. Patients who have had previous genetic testing*, including WES or WGS;
  3. Those with no third-party payer insurance, unable to receive standard of care diagnosis and therapeutic approaches;
  4. Candidates who have already received a diagnosis.

    • Note: Karyotype or microarray testing that did not yield a definitive diagnosis should not be considered as an excluding factor.

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): NCT02699190

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Contact: Omar Sherbini, MPH 215-590-3068

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United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Omar Sherbini, MPH    215-590-3068   
Principal Investigator: Adeline Vanderver, MD         
Sponsors and Collaborators
Children's Hospital of Philadelphia
Illumina, Inc.
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Principal Investigator: Adeline Vanderver, MD Children's Hospital of Philadelphia
  Study Documents (Full-Text)

Documents provided by Adeline Vanderver, MD, Children's Hospital of Philadelphia:
Informed Consent Form  [PDF] December 14, 2018

Additional Information:

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Responsible Party: Adeline Vanderver, MD, Principal Investigator, Children's Hospital of Philadelphia Identifier: NCT02699190    
Other Study ID Numbers: 16-013213
First Posted: March 4, 2016    Key Record Dates
Last Update Posted: September 9, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data (IPD) only available to principal investigator, co-investigators, and trial staff.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Adeline Vanderver, MD, Children's Hospital of Philadelphia:
White Matter Disease
Whole Genome Sequencing
Additional relevant MeSH terms:
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Brain Diseases
Central Nervous System Diseases
Nervous System Diseases