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

NCT02699190 | Completed Results

• 1 other identifier: 16-013213
• Study Type: observational
• Target: 236
• Locations: 1 country
• Sites: 1

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.

Conditions

Leukodystrophy; White Matter Disease; 4H Syndrome; Adrenoleukodystrophy; AMN; ALD; ALD (Adrenoleukodystrophy); X-linked Adrenoleukodystrophy; X-ALD; Adrenomyeloneuropathy; Aicardi Goutieres Syndrome; AGS; Alexander Disease; Alexanders Leukodystrophy; AxD; ADLD; Canavan Disease; CTX; Cerebrotendinous Xanthomatoses; Krabbe Disease; GALC Deficiency; Globoid Leukodystrophy; TUBB4A-Related Leukodystrophy; H-ABC - Hypomyelination, Atrophy of Basal Ganglia and Cerebellum; HBSL; HBSL - Hypomyelination, Brain Stem, Spinal Cord, Leg Spasticity; LBSL; Leukoencephalopathy With Brain Stem and Spinal Cord Involvement and High Lactate Syndrome (Disorder); Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation; ALSP; CSF1R Gene Mutation; HCC - Hypomyelination and Congenital Cataract; MLC1; Megalencephalic Leukoencephalopathy With Subcortical Cysts 1; MLD; Metachromatic Leukodystrophy; PMD; Pelizaeus-Merzbacher Disease; PLP1 Null Syndrome; PLP1 Gene Duplication | Blood or Tissue | Mutations; Pelizaeus-Merzbacher-Like Disease, 1; Peroxisomal Biogenesis Disorder; Zellweger Syndrome; Refsum Disease; Salla Disease; Sialic Storage Disease; Sjögren; Sjogren-Larsson Syndrome; Van Der Knapp Disease; Vanishing White Matter Disease; Charcot-Marie-Tooth; CMT; Mct8 (Slc16A2)-Specific Thyroid Hormone Cell Transporter Deficiency; Allan-Herndon-Dudley Syndrome; Cadasil; Cockayne Syndrome; Multiple Sulfatase Deficiency; Gangliosidoses; GM2 Gangliosidosis; BPAN; Labrune Syndrome; LCC; Mucopolysaccharidoses; TBCK-Related Intellectual Disability Syndrome

Keywords

Leukodystrophy; White Matter Disease; Whole Genome Sequencing; WGS

Outcome Measures

Primary Outcomes (1)

• 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.

  12 months

Secondary Outcomes (1)

• Changes in Clinical Management (Resulting From WGS)

  12 months

Study Arms (1)

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.

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead

Study Sites (1)

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (10)

• Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009 Nov;15(6):319-28. doi: 10.1097/NRL.0b013e3181b287c8.

  PMID: 19901710 BACKGROUND

• Bonkowsky JL, Nelson C, Kingston JL, Filloux FM, Mundorff MB, Srivastava R. The burden of inherited leukodystrophies in children. Neurology. 2010 Aug 24;75(8):718-25. doi: 10.1212/WNL.0b013e3181eee46b. Epub 2010 Jul 21.

  PMID: 20660364 BACKGROUND

• Vanderver A, Hussey H, Schmidt JL, Pastor W, Hoffman HJ. Relative incidence of inherited white matter disorders in childhood to acquired pediatric demyelinating disorders. Semin Pediatr Neurol. 2012 Dec;19(4):219-23. doi: 10.1016/j.spen.2012.10.001.

  PMID: 23245555 BACKGROUND

• Richards J, Korgenski EK, Srivastava R, Bonkowsky JL. Costs of the diagnostic odyssey in children with inherited leukodystrophies. Neurology. 2015 Sep 29;85(13):1167-70. doi: 10.1212/WNL.0000000000001974. Epub 2015 Aug 28.

  PMID: 26320197 BACKGROUND

• Richards J, Korgenski EK, Taft RJ, Vanderver A, Bonkowsky JL. Targeted leukodystrophy diagnosis based on charges and yields for testing. Am J Med Genet A. 2015 Nov;167A(11):2541-3. doi: 10.1002/ajmg.a.37215. Epub 2015 Jul 16.

  PMID: 26183797 BACKGROUND

• Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011 Sep 27;12(11):745-55. doi: 10.1038/nrg3031.

  PMID: 21946919 BACKGROUND

• Srivastava S, Cohen JS, Vernon H, Baranano K, McClellan R, Jamal L, Naidu S, Fatemi A. Clinical whole exome sequencing in child neurology practice. Ann Neurol. 2014 Oct;76(4):473-83. doi: 10.1002/ana.24251. Epub 2014 Aug 30.

  PMID: 25131622 BACKGROUND

• Vanderver A, Simons C, Helman G, Crawford J, Wolf NI, Bernard G, Pizzino A, Schmidt JL, Takanohashi A, Miller D, Khouzam A, Rajan V, Ramos E, Chowdhury S, Hambuch T, Ru K, Baillie GJ, Grimmond SM, Caldovic L, Devaney J, Bloom M, Evans SH, Murphy JLP, McNeill N, Fogel BL; Leukodystrophy Study Group; Schiffmann R, van der Knaap MS, Taft RJ. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol. 2016 Jun;79(6):1031-1037. doi: 10.1002/ana.24650. Epub 2016 May 9.

  PMID: 27159321 BACKGROUND

• Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009 Feb 24;72(8):750-9. doi: 10.1212/01.wnl.0000343049.00540.c8.

  PMID: 19237705 BACKGROUND

• Vanderver A, Bernard G, Helman G, Sherbini O, Boeck R, Cohn J, Collins A, Demarest S, Dobbins K, Emrick L, Fraser JL, Masser-Frye D, Hayward J, Karmarkar S, Keller S, Mirrop S, Mitchell W, Pathak S, Sherr E, van Haren K, Waters E, Wilson JL, Zhorne L, Schiffmann R, van der Knaap MS, Pizzino A, Dubbs H, Shults J, Simons C, Taft RJ; LeukoSEQ Workgroup. Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders. Ann Neurol. 2020 Aug;88(2):264-273. doi: 10.1002/ana.25757. Epub 2020 Jun 9.

  PMID: 32342562 DERIVED

Related Links

• CHOP Leukodystrophy Center Research Portal

MeSH Terms

Conditions

Leukoencephalopathies; Attention Deficit Disorder with Hyperactivity; Adrenoleukodystrophy; Aicardi-Goutieres syndrome; Alexander Disease; Alexanders leukodystrophy; Canavan Disease; Xanthomatosis, Cerebrotendinous; Leukodystrophy, Globoid Cell; Leukodystrophy, Hypomyelinating, 6; Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation; Leukodystrophy, Hypomyelinating, 5; Megalencephalic leukoencephalopathy with subcortical cysts; Leukodystrophy, Metachromatic; Pelizaeus-Merzbacher Disease; Leukodystrophy, Hypomyelinating, 2; Peroxisomal Disorders; Zellweger Syndrome; Refsum Disease; Sialic Acid Storage Disease; Sjogren's Syndrome; Sjogren-Larsson Syndrome; Charcot-Marie-Tooth Disease; Allan-Herndon-Dudley syndrome; CADASIL; Cockayne Syndrome; Multiple Sulfatase Deficiency Disease; Gangliosidoses; Gangliosidoses, GM2; Leukoencephalopathy Brain Calcifications and Cysts; Mucopolysaccharidoses

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Attention Deficit and Disruptive Behavior Disorders; Neurodevelopmental Disorders; Mental Disorders; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Hereditary Central Nervous System Demyelinating Diseases; Demyelinating Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases; Neurodegenerative Diseases; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Xanthomatosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lysosomal Storage Diseases; Sulfatidosis; Liver Diseases; Digestive System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Arthritis, Rheumatoid; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Xerostomia; Salivary Gland Diseases; Mouth Diseases; Stomatognathic Diseases; Dry Eye Syndromes; Lacrimal Apparatus Diseases; Eye Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Ichthyosis; Skin Abnormalities; Skin Diseases, Genetic; Infant, Newborn, Diseases; Keratosis; Skin Diseases; Cerebral Infarction; Brain Infarction; Brain Ischemia; Cerebrovascular Disorders; Cerebral Small Vessel Diseases; Dementia, Vascular; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Stroke; Dementia; Vascular Diseases; Cardiovascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Dwarfism; Bone Diseases, Developmental; Bone Diseases; DNA Repair-Deficiency Disorders; Carbohydrate Metabolism, Inborn Errors; Mucinoses

Results Point of Contact

• Title: Dr. Adeline Vanderver
• Organization: The Children's Hospital of Philadelphia

vandervera@chop.edu

215-590-1719

Study Officials

• Adeline Vanderver, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Program Director, Leukodystrophy Center

Study Record Dates

• First Submitted: February 16, 2016
• First Posted: March 4, 2016
• Study Start: January 6, 2017
• Primary Completion: October 31, 2023
• Study Completion: October 31, 2024
• Last Updated: November 10, 2025
• Results First Posted: June 15, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)