LeukoSEQ: Whole Genome Sequencing as a… | Clinical Trial

Key information

Conditions

Leukodystrophy 4H Syndrome ADLD AGS ALD ALD (Adrenoleukodystrophy) ALSP AMN Abnormalities, Multiple Adrenal Gland Diseases Adrenal Insufficiency Adrenoleukodystrophy Adrenomyeloneuropathy Aicardi Goutieres Syndrome Aicardi-Goutieres syndrome Alexander Disease Alexanders Leukodystrophy Allan-Herndon-Dudley Syndrome Arthritis Arthritis, Rheumatoid Attention Deficit Disorder with Hyperactivity Attention Deficit and Disruptive Behavior Disorders Autoimmune Diseases AxD BPAN Bone Diseases Bone Diseases, Developmental Brain Diseases Brain Diseases, Metabolic Brain Diseases, Metabolic, Inborn Brain Infarction Brain Ischemia CADASIL CMT CSF1R Gene Mutation CTX Canavan Disease Carbohydrate Metabolism, Inborn Errors Cardiovascular Diseases Central Nervous System Diseases Cerebral Arterial Diseases Cerebral Infarction Cerebral Small Vessel Diseases Cerebrotendinous Xanthomatoses Cerebrovascular Disorders Charcot-Marie-Tooth Charcot-Marie-Tooth Disease Cockayne Syndrome Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Connective Tissue Diseases DNA Repair-Deficiency Disorders Dementia Dementia, Vascular Demyelinating Diseases Digestive System Diseases Dry Eye Syndromes Dwarfism Endocrine System Diseases Eye Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications GALC Deficiency GM2 Gangliosidosis Gangliosidoses Gangliosidoses, GM2 Genetic Diseases, Inborn Genetic Diseases, X-Linked Globoid Leukodystrophy H-ABC - Hypomyelination, Atrophy of Basal Ganglia and Cerebellum HBSL HBSL - Hypomyelination, Brain Stem, Spinal Cord, Leg Spasticity HCC - Hypomyelination and Congenital Cataract Hereditary Central Nervous System Demyelinating Diseases Hereditary Sensory and Motor Neuropathy Heredodegenerative Disorders, Nervous System Ichthyosis Immune System Diseases Infant, Newborn, Diseases Infarction Intellectual Disability Intracranial Arterial Diseases Ischemia Joint Diseases Keratosis Kidney Diseases Krabbe Disease LBSL LCC Labrune Syndrome Lacrimal Apparatus Diseases Leukodystrophy, Globoid Cell Leukodystrophy, Hypomyelinating, 2 Leukodystrophy, Hypomyelinating, 5 Leukodystrophy, Hypomyelinating, 6 Leukodystrophy, Metachromatic Leukoencephalopathies Leukoencephalopathy Brain Calcifications and Cysts Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and High Lactate Syndrome (Disorder) Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation Lipid Metabolism Disorders Lipid Metabolism, Inborn Errors Lipidoses Liver Diseases Lysosomal Storage Diseases Lysosomal Storage Diseases, Nervous System MLC1 MLD Male Urogenital Diseases Mct8 (Slc16A2)-Specific Thyroid Hormone Cell Transporter Deficiency Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 Megalencephalic leukoencephalopathy with subcortical cysts Mental Disorders Metabolic Diseases Metabolism, Inborn Errors Metachromatic Leukodystrophy Mouth Diseases Mucinoses Mucopolysaccharidoses Multiple Sulfatase Deficiency Multiple Sulfatase Deficiency Disease Musculoskeletal Diseases Necrosis Nervous System Diseases Nervous System Malformations Neurobehavioral Manifestations Neurodegenerative Diseases Neurodevelopmental Disorders Neurologic Manifestations Neuromuscular Diseases Nutritional and Metabolic Diseases PLP1 Gene Duplication &#X7C; Blood or Tissue &#X7C; Mutations PLP1 Null Syndrome PMD Pathologic Processes Pathological Conditions, Signs and Symptoms Pelizaeus-Merzbacher Disease Pelizaeus-Merzbacher-Like Disease, 1 Peripheral Nervous System Diseases Peroxisomal Biogenesis Disorder Peroxisomal Disorders Polyneuropathies Refsum Disease Rheumatic Diseases Salivary Gland Diseases Salla Disease Sialic Acid Storage Disease Sialic Storage Disease Sjogren's Syndrome Sjogren-Larsson Syndrome Sjögren Skin Abnormalities Skin Diseases Skin Diseases, Genetic Skin and Connective Tissue Diseases Sphingolipidoses Stomatognathic Diseases Stroke Sulfatidosis TBCK-Related Intellectual Disability Syndrome TUBB4A-Related Leukodystrophy Urogenital Diseases Urologic Diseases Van Der Knapp Disease Vanishing White Matter Disease Vascular Diseases White Matter Disease X-ALD X-Linked Intellectual Disability X-linked Adrenoleukodystrophy Xanthomatosis Xanthomatosis, Cerebrotendinous Xerostomia Zellweger Syndrome

Age range

Up to 18 year

Sex eligibility

All sexes

Study type

Observational

Primary location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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;
No pre-existing genetic diagnosis;
A clinical decision has been made to perform WGS;
Less than 18 years of age (exception for the affected sibling of the proband);
Availability of both biologic parents for blood sampling;
Availability of both biological parents to provide informed consent;
Concurrently enrolled in CHOP IRB 14-011236 (Myelin Disorders Biorepository Project)

Exclusion criteria

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

Treatment and study plan

Primary outcomes

Changes in Diagnosis Status (Resulting From WGS)

Time frame: 12 months

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.

Secondary outcomes

Changes in Clinical Management (Resulting From WGS)

Time frame: 12 months

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.

Sponsors and collaborators

Lead sponsor

Children's Hospital of Philadelphia

Other

Registry information

Important dates

Study start: 2017
Primary completion: 2023
Study completion: 2024
First posted: Mar 4, 2016
Registry last updated: Nov 10, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Published trials that share one or more normalized conditions with this study.

Recruiting