Clinical trial NCT02699190: LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
Official title: LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
Study type: OBSERVATIONAL
Overall status: COMPLETED
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 &#X7C; Blood or Tissue &#X7C; 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
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
First posted: 2016-03-04
Enrollment: 236
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed 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 (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.

Eligibility criteria: 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 (exception for the affected sibling of the proband);
5. Availability of both biologic parents for blood sampling;
6. Availability of both biological parents to provide informed consent;
7. Concurrently enrolled in CHOP IRB 14-011236 (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.

Primary outcomes:
measure: Changes in Diagnosis Status (Resulting From WGS)
timeFrame: 12 months
Secondary outcomes:
measure: Changes in Clinical Management (Resulting From WGS)
timeFrame: 12 months
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Adeline Vanderver, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009 Nov;15(6):319-28. doi: 10.1097/NRL.0b013e3181b287c8.
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.
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.
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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.
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.
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citation: 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.