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Whole exome sequencing in patients with white matter abnormalities
Open accessAbstract
Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031–1037
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“Nevertheless, the percentage of leukodystrophy cases without a specific diagnosis has been estimated to be 20–30% [7,39,40].”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [7]
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“NGS genetic testing, including gene panel testing, WES, or whole genome sequencing (WGS), is the most successful approach for diagnosing rare diseases with the highest diagnostic yield [7,37].”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Genetic screening using next-generation sequencing (NGS) is the most successful approach with the highest diagnostic yield in cases of underlying genetic disorders, such as CALD, and provides the fastest results [7,8].”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Trio-WES has substantially increased the number of known leukodystrophies and improved diagnoses [7,8,39].”
From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previously, we reported on a cohort of 191 families with a suspected leukodystrophy, of which 71 were persistently unsolved despite targeted molecular and enzymatic testing and 19 were lost to follow‐up.1”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [1]
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“Trio‐or‐greater exome sequencing analysis resolved 42% (30/71) of unsolved cases, which, in combination with standard of care approaches, yielded a 77% overall diagnostic rate from 172 families available for testing.”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [1]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Thirty cases were solved by exome sequencing,1 and in this study, genome sequencing established a diagnosis in an additional 14 families yielding a 20% improvement, and an overall diagnostic efficacy of NGS of genome or exome sequencing increased to 44/71 (62%) and in total resolution of 145/172 (84%) of the original testable cohort.”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [1]
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“The duplication was previously undetected by exome sequencing due to a lack of coverage as it lies in the middle of a 110 nucleotide block of a ~ 95% GC‐rich region (Fig. 1B).1”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [1]
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“Stringent variant filtering performed during the prior exome sequencing analysis excluded this intronic variant and precluded a diagnosis.1”
From Genome sequencing in persistently unsolved white matter disorders (2020) · cites this paper as [1]
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Metadata
- Authors
- Vanderver, A., Simons, C., Helman, G., Crawford, J., Wolf, N. I., Bernard, G., Pizzino, A., Schmidt, J. L., Takanohashi, A., Miller, D., Khouzam, A., Rajan, V., Ramos, E., Chowdhury, S., Hambuch, T., Ru, K., Baillie, G. J., Grimmond, S. M., Caldovic, L., Devaney, J., Bloom, M., Evans, S. H., Murphy, J. L. P., McNeill, N., Fogel, B. L., the Leukodystrophy Study Group, Schiffmann, R., van der Knaap, M. S., & Taft, R. J.
- Affiliations
- Children's National (US)
- The University of Queensland (AU)
- Amsterdam Neuroscience (NL)
- Montreal Children's Hospital (CA)
- Illumina (United States) (US)
- Institute for Metabolic Disease Baylor Research Institute Dallas TX
- University of California, Los Angeles (US)
- Corresponding author
- Vanderver, Adeline
- Simons, Cas
- ORCID
- Vanderver, Adeline
- Simons, Cas
- Helman, Guy
- Crawford, Joanna
- Wolf, Nicole I.
- Bernard, Geneviève
- Pizzino, Amy
- Schmidt, Johanna L.
- Takanohashi, Asako
- Ramos, Erica
- Chowdhury, Shimul
- Hambuch, Tina
- Baillie, Gregory J.
- Grimmond, Sean M.
- Caldovic, Ljubica
- Devaney, Joseph
- Evans, Sarah H.
- Murphy, Jennifer L. P.
- McNeill, Nathan
- Fogel, Brent L.
- Schiffmann, Raphael
- van der Knaap, Marjo S.
- Taft, Ryan J.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2016-05-09
- Volume
- 79
- Issue
- 6
- Pages
- 1031-1037
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC5354169
- OpenAlex
- W2346093359
- Cited by
- 145
- References
- 36
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 12 · 2023: 17 · 2022: 13 · 2021: 21 · 2020: 16 · 2019: 17 · 2018: 22 · 2017: 11 · 2016: 2
- FWCI
- 14.00
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- Santé
- Australian Research Council
- National Health and Medical Research Council (APP1068278)
- ZonMw (91211005)
- National Institute of Mental Health (K08MH086297)
- National Institute of Neurological Disorders and Stroke (R01NS082094)
- National Center for Advancing Translational Sciences (UL1TR000075)
- Myelin Project
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- white matter abnormalities, leukodystrophy, pathogenic variants, trio exome sequencing, genetic diagnosis, hereditary leukodystrophy
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, DNA Mutational Analysis, Female, Humans, Male, Mutation, Young Adult, Leukoencephalopathies, Exome, White Matter
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