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

Adrenoleukodystrophy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02699190
• Other study ID #: 16-013213
• Status: Active, not recruiting
• Start date: January 6, 2017
• Est. completion date: December 2024

Study information

• Verified date: May 2024
• Source: Children's Hospital of Philadelphia
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

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 technologies (NGS) 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 clinical management in subjects affected by undiagnosed genetic disorders of the white matter of the brain relative to standard diagnostic approaches. We anticipate that WGS will produce measurable downstream changes in clinical management, as defined by disease-specific screening for complications or implementation of disease-specific therapeutic approaches.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 450
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

1. 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;

2. No pre-existing genetic diagnosis;

3. A clinical decision has been made to perform WGS;

4. Less than 18 years of age;

5. Availability of both biologic parents for blood sampling;

6. Availability both biological parents to provide informed consent;

7. Concurrently enrolled in CHOP IRB 14-011236 (New Diagnostic Approaches in Leukodystrophy - The Myelin Disorders Biorepository Project)

Exclusion Criteria:

1. Candidates with acquired disorders, including infection, acute disseminated encephalomyelitis (ADEM), multiple sclerosis, vasculitis or toxic leukoencephalopathies;

2. Patients who have had previous genetic testing*, including WES or WGS;

3. Those with no third-party payer insurance, unable to receive standard of care diagnosis and therapeutic approaches;

4. 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.

Related Conditions & MeSH terms

• Adrenoleukodystrophy
• Adrenomyeloneuropathy
• Aicardi Goutieres Syndrome
• ALD
• ALD (Adrenoleukodystrophy)
• Alexander Disease
• Allan-Herndon-Dudley Syndrome
• ALSP
• AMN
• Cadasil
• Canavan Disease
• Charcot-Marie-Tooth
• Charcot-Marie-Tooth Disease
• CMT
• Cockayne Syndrome
• CTX
• Gangliosidoses
• Gangliosidoses, GM2
• GM2 Gangliosidosis
• Hereditary Sensory and Motor Neuropathy
• Intellectual Disability
• Krabbe Disease
• LBSL
• Leukodystrophy
• Leukodystrophy, Globoid Cell
• Leukodystrophy, Metachromatic
• Leukoencephalopathies
• Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation
• Mct8 (Slc16A2)-Specific Thyroid Hormone Cell Transporter Deficiency
• Metachromatic Leukodystrophy
• MLD
• Mucopolysaccharidoses
• Multiple Sulfatase Deficiency Disease
• Nerve Compression Syndromes
• Pelizaeus-Merzbacher Disease
• Peroxisomal Disorders
• PMD
• Refsum Disease
• Sjogren's Syndrome
• Sjogren-Larsson Syndrome
• Syndrome
• Tay-Sachs Disease
• Vanishing White Matter Disease
• White Matter Disease
• X-ALD
• X-linked Adrenoleukodystrophy
• Xanthomatosis, Cerebrotendinous
• Zellweger Syndrome

Locations

Country	Name	City	State
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital of Philadelphia

Country where clinical trial is conducted

United States, 

References & Publications (9)

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in Clinical Management (Resulting from WGS)	The primary objective of this study is to evaluate changes in clinical management between the study cohort, who will undergo whole genome sequencing (WGS) as part of clinical care, and a historical cohort of patients whose diagnoses were established using standard (i.e. non-WGS) diagnostic approaches. Differences in clinical management will be measured at six months following disclosure of results.	01/06/2017 - 07/28/2022
Secondary	Time to Implementation of Changes in Clinical Management (Resulting from WGS)	Determine whether time to implementation of clinical management approaches differs between subjects who received whole genome sequencing over standard diagnostic approaches.	01/06/2017 - 07/28/2022

External Links

•   CHOP Leukodystrophy Center Research Portal