TY - JOUR
T1 - Unclassified white matter disorders
T2 - A diagnostic journey requiring close collaboration between clinical and laboratory services
AU - Stutterd, C. A.
AU - Vanderver, A.
AU - Lockhart, P. J.
AU - Helman, G.
AU - Pope, K.
AU - Uebergang, E.
AU - Love, C.
AU - Delatycki, M. B.
AU - Thorburn, D.
AU - Mackay, M. T.
AU - Peters, H.
AU - Kornberg, A. J.
AU - Patel, C.
AU - Rodriguez-Casero, V.
AU - Waak, M.
AU - Silberstein, J.
AU - Sinclair, A.
AU - Nolan, M.
AU - Field, M.
AU - Davis, M. R.
AU - Fahey, M.
AU - Scheffer, I. E.
AU - Freeman, J. L.
AU - Wolf, N. I.
AU - Taft, R. J.
AU - van der Knaap, M. S.
AU - Simons, C.
AU - Leventer, R. J.
N1 - Funding Information: CAS was supported by NHMRC Postgraduate Scholarship (ID: APP1133266 ) and the Royal Children's Hospital/Murdoch Children's Research Institute Flora Suttie Neurogenetics Fellowship made possible by the Thyne-Reid Foundation and the Macquarie Foundation . RJL is supported by a Melbourne Children's Clinician Scientist Fellowship . This work was supported by the Massimo's Mission Leukodystrophy Flagship funded by the Australian Government Medical Research Futures Fund . This work was supported by the Victorian Government's Operational Infrastructure Support Program and Australian Government National Health and Medical Research Council Independent Research Institute Infrastructure Support Scheme (NHMRC IRIISS) and NHMRC Project Grant 1068278 . AV is supported by the Kamens Chair in Translational Neurotherapeutics. MSvdK receives research support from NWO, ZonMw, European Leukodystrophy Foundation, Nederlandse Hersenstichting, Vanishing White Matter Foundation, Chloe Saxby and VWM Disease Incorporated, and VWM Families Foundation Inc. IES is supported by grants and fellowships from the National Health and Medical Research Council of Australia. NIW receives research support from Metakids and ZonMW The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. Publisher Copyright: © 2022
PY - 2022/9/1
Y1 - 2022/9/1
N2 - Background: 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 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. Aim: 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. Methods: 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. Results: 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 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. Conclusions: 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 prognostication, appropriate management, and accurate reproductive counseling.
AB - Background: 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 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. Aim: 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. Methods: 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. Results: 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 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. Conclusions: 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 prognostication, appropriate management, and accurate reproductive counseling.
KW - Brain diseases
KW - Genetic testing
KW - Genomics
KW - High-throughput nucleotide sequencing
KW - Phenotype
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U2 - https://doi.org/10.1016/j.ejmg.2022.104551
DO - https://doi.org/10.1016/j.ejmg.2022.104551
M3 - Article
C2 - 35803560
SN - 1769-7212
VL - 65
SP - 1
EP - 9
JO - European journal of medical genetics
JF - European journal of medical genetics
IS - 9
M1 - 104551
ER -