Please use this identifier to cite or link to this item:
Title: Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.
Austin Authors: Stutterd, C A;Vanderver, A;Lockhart, P J;Helman, G;Pope, K;Uebergang, E;Love, C;Delatycki, M B;Thorburn, D;Mackay, M T;Peters, H;Kornberg, A J;Patel, C;Rodriguez-Casero, V;Waak, M;Silberstein, J;Sinclair, A;Nolan, M;Field, M;Davis, M R;Fahey, M;Scheffer, Ingrid E ;Freeman, J L;Wolf, N I;Taft, R J;van der Knaap, M S;Simons, C;Leventer, R J
Affiliation: Department of Paediatrics, University of Melbourne, Victoria, Australia..
Medicine (University of Melbourne)
The Florey Institute of Neuroscience and Mental Health
Princess Margaret Hospital, Perth, Western Australia, Australia..
Genetics of Learning Disability (GOLD) Service, Hunter Genetics, Newcastle, New South Wales, Australia..
Department of Diagnostic Genomics, Path West Laboratory Medicine, QEII Medical Centre, Hospital Avenue, Nedlands, WA, Australia..
Department of Paediatrics, Monash University, Victoria, Australia..
Murdoch 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..
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia..
Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands..
Department of Metabolic Medicine, Royal Children's Hospital, Victoria, Australia..
Genetic Health Neurointensivist, 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..
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA..
Department of Neurosciences, Queensland Children's Hospital, Brisbane, Queensland, Australia..
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA..
Department of Paediatric Neurology, Starship Children's Health, Auckland, New Zealand..
Amsterdam Leukodystrophy Center, Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, VU University, Amsterdam Neuroscience, Amsterdam, the Netherlands..
Illumina Inc, San Diego, CA, USA..
Issue Date: 5-Jul-2022 2022
Publication information: European Journal of Medical Genetics 2022; 65(9): 104551
Abstract: Next 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 is 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 less targeted approach to genomic testing is recommended. This 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. Twenty-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. Causative 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 by a current leukodystrophy specific gene panel test. 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. Genetic 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 accurate prognostication, appropriate management, and reproductive counseling.
DOI: 10.1016/j.ejmg.2022.104551
ORCID: 0000-0002-2311-2174
Journal: European journal of medical genetics
PubMed URL: 35803560
PubMed URL:
Type: Journal Article
Subjects: Brain diseases
Genetic testing
High-throughput nucleotide sequencing
White matter
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Jun 7, 2023

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.