An observational study in Leukodystrophy, White Matter Disease and 4H Syndrome, sponsored by Children's Hospital of Philadelphia. Completed at 1 site in United States. Open to participants aged Up to 18 Years. Per ClinicalTrials.gov, last updated 2025-11-10.
Sponsored by Children's Hospital of Philadelphia · Observational
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.
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 (NGS) technologies 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 diagnostic status and clinical management in subjects affected by undiagnosed genetic disorders of the white matter of the brain. We anticipate that WGS will produce measurable downstream changes in diagnostic status and clinical management, as defined by disease-specific screening for complications or implementation of disease-specific therapeutic approaches.
39 studies on the registry are indexed under Leukoencephalopathies; 16 are open to participants now.
This study's enrollment of 236 is above the median of 100 across 28 observational studies indexed under Leukoencephalopathies.
Browse Leukoencephalopathies studies →Children's Hospital of Philadelphia is the lead sponsor of 489 studies on the registry; 90 are open to participants now.
Of its 28 completed or terminated interventional studies of FDA-regulated products, 22 (79%) have results posted.
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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.
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Exclusion Criteria:
Candidates who have already received a diagnosis.
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Changes in Diagnosis Status (Resulting From WGS)
The primary objective of this study is to evaluate changes in diagnostic status in the study cohort for patients who received Whole Genome Sequencing (WGS) as part of clinical care. Differences in diagnostic status will be measured at disclosure of initial results or disclosure of reanalyzed results.
Time frame: 12 months
Changes in Clinical Management (Resulting From WGS)
The secondary objective of this study is to evaluate changes in clinical care in subjects who received a diagnosis through Whole Genome Sequencing (WGS). Differences in clinical care will be evaluated 1 year following disclosure of results.
Time frame: 12 months
| Milestone | Prospective Study Cohort |
|---|---|
| Started | 236 |
| Affected patients | 80 |
| Biological parents | 156 |
| Completed | 236 |
| Not completed | 0 |
The primary objective of this study is to evaluate changes in diagnostic status in the study cohort for patients who received Whole Genome Sequencing (WGS) as part of clinical care. Differences in diagnostic status will be measured at disclosure of initial results or disclosure of reanalyzed results.
| Participants | Prospective Study Cohort |
|---|---|
| Changes in Diagnosis Status (Resulting From WGS) | 45 |
The secondary objective of this study is to evaluate changes in clinical care in subjects who received a diagnosis through Whole Genome Sequencing (WGS). Differences in clinical care will be evaluated 1 year following disclosure of results.
| participants | Prospective Study Cohort |
|---|---|
| Referred to specialists providers for disease monitoring | 37 |
| Received additional targeted screening | 35 |
| Eligible for disease modifying treatment | 8 |
Collected over This study is observational and considered to involve no greater than minimal risk. The primary risk of study participation involves breach of confidentiality due to collection, analysis, and/or retention of Personal Health Information (PHI) from subject medical records. Adverse events were therefore not expected and not collected.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Prospective Study Cohort | — | — | — |
Baseline data was only obtained from affected patients. Biological parents' medical records were collected and reviewed to verify whether the affected patient's genetic variant was pathogenic. Therefore, the baseline analysis population includes the 80 enrolled affected patients and excludes the 156 enrolled biological parents.
| Age, Categorical(Participants) | Prospective Study Cohort |
|---|---|
| <=18 years | 80 |
| Between 18 and 65 years | 0 |
| >=65 years | 0 |
| Sex: Female, Male(Participants) | Prospective Study Cohort |
|---|---|
| Female | 41 |
| Male | 39 |
| Ethnicity (NIH/OMB)(Participants) | Prospective Study Cohort |
|---|---|
| Hispanic or Latino | 2 |
| Not Hispanic or Latino | 0 |
| Unknown or Not Reported | 78 |
| Race (NIH/OMB)(Participants) | Prospective Study Cohort |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 6 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 4 |
| White | 60 |
| More than one race | 4 |
| Unknown or Not Reported | 6 |
| Region of Enrollment(participants) | Prospective Study Cohort |
|---|---|
| United States | 80 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No — Individual participant data (IPD) only available to principal investigator, co-investigators, and trial staff.
Ran from Jan 2017 to primary completion in Oct 2023, 81 months.
Results were first posted in Jun 2025, 1 year 7 months after primary completion.
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This study is completed, as verified in Nov 2025. You cannot join it, but the record below documents what was studied.
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