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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2017 by Children's Hospital of Philadelphia
Illumina, Inc.
Massachusetts General Hospital
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Children's Hospital of Philadelphia Identifier:
First received: February 16, 2016
Last updated: April 19, 2017
Last verified: April 2017
The purpose of this study is to establish the ability of Next-Generation Sequencing (NGS) technologies to provide a diagnosis in a group of participants with suspected leukodystrophy as determined by clinical symptoms, including MRI imaging, but without a specific genetic diagnosis. Cost-effectiveness and clinical utility of whole genome sequencing will also be investigated as part of the study.

Condition Intervention
White Matter Disease
Other: Whole Genome Sequencing (WGS)
Other: Standard Clinical Care and Diagnostic Approaches

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Participant, Care Provider, Investigator
Primary Purpose: Diagnostic
Official Title: LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies

Resource links provided by NLM:

Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • Number of Successful Diagnoses [ Time Frame: 01/06/2017 - 10/01/2018 ]
  • Time to Diagnosis [ Time Frame: 01/06/2017 - 10/01/2018 ]

Estimated Enrollment: 50
Actual Study Start Date: January 6, 2017
Estimated Study Completion Date: April 1, 2020
Estimated Primary Completion Date: October 1, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard Clinical Care followed by WGS

Subjects will continue to receive standard clinical care according to existing algorithms based on MRI pattern recognition and will receive clinically indicated testing as considered appropriate by the expert clinician. This may include further clinical diagnostic testing as ordered by a neurologist or geneticist with specialized experience in leukodystrophy. The diagnostic testing must not include NGS (WES or WGS), though enzymatic assays, analytic testing, or sequencing by single or targeted panels will be permitted.

Crossover to Experimental Arm will occur if no diagnosis has been achieved within four (4) months of study enrollment.

Other: Standard Clinical Care and Diagnostic Approaches
Any diagnostic testing other than whole genome sequencing (WGS) that may be ordered in the context of a participant's routine clinical care, including scheduled and unscheduled hospital and/or outpatient visits clinic visits.
Experimental: Immediate WGS
Participants will undergo immediate WGS-based testing in a CLIA/CAP-certified laboratory. This testing will include tiered analysis of leukodystrophy associated genes, as defined by those disorders characterized by experts as resulting in leukodystrophies or genetic leukoencephalopathies. These results will be filtered for structural and copy number variations, and followed-up with comprehensive analysis of novel genes in coding regions if participants remain unsolved.
Other: Whole Genome Sequencing (WGS)
Whole genome sequencing (WGS), widely regarded as the most comprehensive method for analyzing the genome, will be performed in Illumina's CLIA/CAP-certified Clinical Services Laboratory.

Detailed Description:

The leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Leukodystrophies are a group of approximately 30 genetic diseases that primarily affect the white matter of the central nervous system (CNS) and remain a diagnostic challenge for clinicians and researchers. As a whole, leukodystrophies are relatively common (approximately 1 in 7000 births). This genetically heterogeneous set of disorders is categorized based on initial findings of white matter abnormalities in the CNS. Historically, these abnormalities were identified using gross pathology. More recently, neuroimagery has been used for diagnostic purposes. However, more than half of the suspected leukodystrophies do not have a definitive diagnosis, and are 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. In general, NGS has the potential to revolutionize medical research and diagnostics, particularly for rare diseases - 80% of which are genetic in origin. In the last two years, the pace of discovery has increased at a remarkable rate due to the use of whole genome sequencing (WGS) and whole exome sequencing (WES). Recent reports suggest that WES can yield insights into previously ambiguous rare genetic disorders. For example, large-scale WES projects have been used to identify new nosologic entities using clinical and molecular data in adult onset leukodystrophy, neurodevelopmental disorders, epilepsy/ epileptic encephalopathies, degenerative ataxia, and intellectual disability. In clinical settings, WES has also been shown to provide diagnoses for atypical presentations of established disorders. Overall, diagnostic yields for large disease cohorts range from 16-53%.

Despite these advances in diagnostic efficacy, there are still significant issues with respect to implementation of NGS in clinical settings. Given the unmet diagnostic need amongst patients with persistently unresolved white matter disorders, and the potential for agnostic NGS testing to clarify these cases, the investigators propose a randomized controlled trial (RCT) of 200 leukodystrophy patients 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. All participants will undergo WGS in parallel to standard clinical testing in a staggered fashion. The WGS testing will be performed in a clinical services laboratory that is certified under Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists (CAP). This approach aims to assess the diagnostic validity and utility of NGS approaches, with primary outcome measures including time to diagnosis and whether or not a diagnosis was achieved.

The investigators anticipate that the results of this study will serve as a pilot for similar approaches in other rare disease cohorts, and will ultimately help in establishing the utility of WGS as a first-line diagnostic tool for patients with suspected genetic conditions.


Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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;
  • White matter abnormality identified on MRI less than two months prior to enrollment;
  • No evidence of an acquired cause for the white matter abnormalities (infection, trauma, birth related injury, etc.;
  • No pre-existing diagnosis;
  • Less than 18 years of age at time of enrollment;
  • Availability of both biologic parents for blood sampling as part of a routine clinical test.

Exclusion Criteria:

  • Candidates with acquired disorders, including infection, acute disseminated encephalomyelitis (ADEM), multiple sclerosis, vasculitis or toxic leukoencephalopathies;
  • Candidates who have previous or pending genetic testing results, including WES, WGS, or iterative panel testing of more than 20 cumulative genes. Karyotype or microarray testing that did not yield a definitive diagnosis will not be considered as an excluding factor;
  • Candidates with no third-party payer insurance, or who are otherwise unable to receive standard of care diagnosis and therapeutic approaches in the United States;
  • Candidates that have already received a definitive diagnosis.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02699190

Contact: Omar Sherbini, MPH (215) 590-2575

United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Omar Sherbini, MPH    215-590-2575   
Principal Investigator: Adeline Vanderver, MD         
Sponsors and Collaborators
Children's Hospital of Philadelphia
Illumina, Inc.
Massachusetts General Hospital
National Institutes of Health (NIH)
Principal Investigator: Adeline Vanderver, MD Children's Hospital of Philadelphia
  More Information

Responsible Party: Children's Hospital of Philadelphia Identifier: NCT02699190     History of Changes
Other Study ID Numbers: 16-013213
Study First Received: February 16, 2016
Last Updated: April 19, 2017
Individual Participant Data  
Plan to Share IPD: No
Plan Description: Individual participant data (IPD) only available to principal investigator, co-investigators, and trial staff.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Children's Hospital of Philadelphia:
White Matter Disease
Whole Genome Sequencing

Additional relevant MeSH terms:
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases processed this record on April 28, 2017