LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
|Leukodystrophy White Matter Disease||Other: Whole Genome Sequencing (WGS) Other: Standard Clinical Care and Diagnostic Approaches|
|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|
- Number of Successful Diagnoses [ Time Frame: 01/06/2017 - 10/01/2018 ]
- Time to Diagnosis [ Time Frame: 01/06/2017 - 10/01/2018 ]
|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)|
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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02699190
|Contact: Omar Sherbini, MPH||(215) firstname.lastname@example.org|
|United States, Pennsylvania|
|The Children's Hospital of Philadelphia||Recruiting|
|Philadelphia, Pennsylvania, United States, 19104|
|Contact: Omar Sherbini, MPH 215-590-2575 email@example.com|
|Principal Investigator: Adeline Vanderver, MD|
|Principal Investigator:||Adeline Vanderver, MD||Children's Hospital of Philadelphia|