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; H. Peters; A. J. Kornberg; C. Patel; V. Rodriguez-Casero; M. Waak; J. Silberstein; A. Sinclair; M. Nolan; M. Field; M. R. Davis; M. Fahey; I. E. Scheffer; J. L. Freeman; N. I. Wolf; R. J. Taft; M. S. van der Knaap; C. Simons; R. J. Leventer

doi:10.1016/j.ejmg.2022.104551

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, H. Peters, A. J. Kornberg, C. Patel, V. Rodriguez-Casero, M. Waak, J. Silberstein, A. Sinclair, M. Nolan, M. Field, M. R. DavisM. Fahey, I. E. Scheffer, J. L. Freeman, N. I. Wolf, R. J. Taft, M. S. van der Knaap, C. Simons, R. J. Leventer^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	104551
Pages (from-to)	1-9
Number of pages	9
Journal	European Journal of Medical Genetics
Volume	65
Issue number	9
Early online date	5 Jul 2022
DOIs	https://doi.org/10.1016/j.ejmg.2022.104551
Publication status	Published - Sept 2022

Bibliographical note

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

Funding

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.

Funders	Funder number
Australian Government Medical Research Futures Fund
Australian Government National Health and Medical Research Council	1068278
European Leukodystrophy Foundation
Macquarie Foundation
Melbourne Children's
Royal Children's Hospital/Murdoch Children's Research Institute Flora Suttie Neurogenetics Fellowship
Thyne-Reid Foundation
VWM Disease Incorporated
VWM Families Foundation Inc
Vanishing White Matter Foundation
National Health and Medical Research Council	APP1133266
National Health and Medical Research Council
ZonMw
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
State Government of Victoria
Hersenstichting

Keywords

Brain diseases
Genetic testing
Genomics
High-throughput nucleotide sequencing
Phenotype

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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., ... Leventer, R. J. (2022). Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services. European Journal of Medical Genetics, 65(9), 1-9. Article 104551. https://doi.org/10.1016/j.ejmg.2022.104551

@article{cba8a24c56a5430ea718140d714c431c,

title = "Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services",

abstract = "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.",

keywords = "Brain diseases, Genetic testing, Genomics, High-throughput nucleotide sequencing, Phenotype",

author = "Stutterd, {C. A.} and A. Vanderver and Lockhart, {P. J.} and G. Helman and K. Pope and E. Uebergang and C. Love and Delatycki, {M. B.} and D. Thorburn and Mackay, {M. T.} and H. Peters and Kornberg, {A. J.} and C. Patel and V. Rodriguez-Casero and M. Waak and J. Silberstein and A. Sinclair and M. Nolan and M. Field and Davis, {M. R.} and M. Fahey and Scheffer, {I. E.} and Freeman, {J. L.} and Wolf, {N. I.} and Taft, {R. J.} and {van der Knaap}, {M. S.} and C. Simons and Leventer, {R. J.}",

note = "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: {\textcopyright} 2022",

year = "2022",

month = sep,

doi = "10.1016/j.ejmg.2022.104551",

language = "English",

volume = "65",

pages = "1--9",

journal = "European Journal of Medical Genetics",

issn = "1769-7212",

publisher = "Elsevier Masson s.r.l.",

number = "9",

}

Stutterd, CA, Vanderver, A, Lockhart, PJ, Helman, G, Pope, K, Uebergang, E, Love, C, Delatycki, MB, Thorburn, D, Mackay, MT, Peters, H, Kornberg, AJ, Patel, C, Rodriguez-Casero, V, Waak, M, Silberstein, J, Sinclair, A, Nolan, M, Field, M, Davis, MR, Fahey, M, Scheffer, IE, Freeman, JL, Wolf, NI, Taft, RJ, van der Knaap, MS, Simons, C & Leventer, RJ 2022, 'Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services', European Journal of Medical Genetics, vol. 65, no. 9, 104551, pp. 1-9. https://doi.org/10.1016/j.ejmg.2022.104551

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

Y1 - 2022/9

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

Abstract

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Keywords

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