Evidence map›Paper›PMID 35803560›Full record

ArticleEuropean journal of medical genetics2022

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

C A Stutterd, A Vanderver, P J Lockhart, G Helman, K Pope, E Uebergang, C Love, M B Delatycki, D Thorburn, M T Mackay and 18 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of medical genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.3field-weighted citation impact, top 45% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed, 5 citations in OpenAlex.

  1. Rigorous genetic diagnosis review in natural history studies.Orphanet journal of rare diseases · 2026
    Article
  2. CharacterizingmedRxiv : the preprint server for health sciences · 2026
    Article
  3. Article
  4. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors at 13 institutions in 4 countries.

C A StutterdMurdoch Children's Research Institute, Victoria, Australia; Department of Neurology, Royal Children's Hospital, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
A VanderverDivision of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
P J LockhartMurdoch Children's Research Institute, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
G HelmanInstitute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
K PopeMurdoch Children's Research Institute, Victoria, Australia.
E UebergangMurdoch Children's Research Institute, Victoria, Australia.
C LoveMurdoch Children's Research Institute, Victoria, Australia.
M B DelatyckiMurdoch Children's Research Institute, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
D ThorburnMurdoch Children's Research Institute, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
M T MackayMurdoch Children's Research Institute, Victoria, Australia; Department of Neurology, Royal Children's Hospital, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
H PetersMurdoch Children's Research Institute, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia; Department of Metabolic Medicine, Royal Children's Hospital, Victoria, Australia.
A J KornbergMurdoch Children's Research Institute, Victoria, Australia; Department of Neurology, Royal Children's Hospital, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
C PatelGenetic Health Queensland, Royal Brisbane and Women's Children's Hospital, South Brisbane Queensland, Australia; Centre for Children's Health Research, The University of Queensland, Queensland, Australia.
V Rodriguez-CaseroMurdoch Children's Research Institute, Victoria, Australia; Department of Neurology, Royal Children's Hospital, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
M WaakCentre for Children's Health Research, The University of Queensland, Queensland, Australia; Department of Neurosciences, Queensland Children's Hospital, Brisbane, Queensland, Australia.
J SilbersteinPrincess Margaret Hospital, Perth, Western Australia, Australia.
A SinclairDepartment of Neurosciences, Queensland Children's Hospital, Brisbane, Queensland, Australia.
M NolanDepartment of Paediatric Neurology, Starship Children's Health, Auckland, New Zealand.
M FieldGenetics of Learning Disability (GOLD) Service, Hunter Genetics, Newcastle, New South Wales, Australia.
M R DavisDepartment of Diagnostic Genomics, Path West Laboratory Medicine, QEII Medical Centre, Hospital Avenue, Nedlands, WA, Australia.
M FaheyDepartment of Paediatrics, Monash University, Victoria, Australia.
I E SchefferMurdoch Children's Research Institute, Victoria, Australia; Department of Neurology, Royal Children's Hospital, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia; Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, 3084, Australia; The Florey Institute of Neuroscience and Mental Health and Murdoch Children's Research Institute, Parkville, Victoria, 3052, Australia.
J L FreemanMurdoch Children's Research Institute, Victoria, Australia; Department of Neurology, Royal Children's Hospital, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia.
N I WolfAmsterdam Leukodystrophy Center, Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University, Amsterdam Neuroscience, Amsterdam, the Netherlands; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
R J TaftIllumina Inc, San Diego, CA, USA.
M S van der KnaapAmsterdam Leukodystrophy Center, Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University, Amsterdam Neuroscience, Amsterdam, the Netherlands; Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
C SimonsMurdoch Children's Research Institute, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia. Electronic address: cas.simons@mcri.edu.au.
R J LeventerMurdoch Children's Research Institute, Victoria, Australia; Department of Neurology, Royal Children's Hospital, Victoria, Australia; Department of Paediatrics, University of Melbourne, Victoria, Australia. Electronic address: richard.leventer@rch.org.au.
Royal Children's Hospital · AUMurdoch Children's Research Institute · AUThe University of Melbourne · AUAmsterdam Neuroscience · NLChildren's Medical Research Institute · AUQueen Elizabeth II Medical Centre · AUChildren's Health Queensland Hospital and Health Service · AUChildren's Hospital of Philadelphia · USHunter Genetics · AUIllumina (United States) · USPrincess Margaret Hospital for Children · AUStarship Children's Health · NZThe University of Queensland · AU

Funding

Validation of the GMFC-MLDU54NS115052 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI Laura Ann Adang, FLORIAN S EICHLER · 2019 to 2026
$14.3M
NINDS NIH HHS U54 NS115052
6 · The paper itself

Abstract

backgroundNext generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended.

aimThis study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic.

methodsTwenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance.

resultsCausative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses.

conclusionsGenetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

Indexed as

LeukoencephalopathiesWhite MatterFlavoproteinsGenetic TestingHigh-Throughput Nucleotide SequencingHumansMitochondrial ProteinsPhenotypePhosphoric Monoester HydrolasesTubulinBolA3 protein, humanFIG4 protein, humanFlavoproteinsMitochondrial ProteinsPhosphoric Monoester HydrolasesTUBB4A protein, humanTubulinBrain diseasesGenetic testingGenomicsHigh-throughput nucleotide sequencingPhenotype

Identifiers

PMID35803560
PMCPMC11479680
OpenAlexW4284687222

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.