Genome sequencing in persistently unsolved white matter disorders

Guy Helman; Bryan R. Lajoie; Joanna Crawford; Asako Takanohashi; Marzena Walkiewicz; Egor Dolzhenko; Andrew M. Gross; Vladimir G. Gainullin; Stephen J. Bent; Emma M. Jenkinson; Sacha Ferdinandusse; Hans R. Waterham; Imen Dorboz; Enrico Bertini; Noriko Miyake; Nicole I. Wolf; Truus E.M. Abbink; Susan M. Kirwin; Christina M. Tan; Grace M. Hobson; Long Guo; Shiro Ikegawa; Amy Pizzino; Johanna L. Schmidt; Genevieve Bernard; Raphael Schiffmann; Marjo S. van der Knaap; Cas Simons; Ryan J. Taft; Adeline Vanderver

doi:10.1002/acn3.50957

Genome sequencing in persistently unsolved white matter disorders

Guy Helman, Bryan R. Lajoie, Joanna Crawford, Asako Takanohashi, Marzena Walkiewicz, Egor Dolzhenko, Andrew M. Gross, Vladimir G. Gainullin, Stephen J. Bent, Emma M. Jenkinson, Sacha Ferdinandusse, Hans R. Waterham, Imen Dorboz, Enrico Bertini, Noriko Miyake, Nicole I. Wolf, Truus E.M. Abbink, Susan M. Kirwin, Christina M. Tan, Grace M. HobsonLong Guo, Shiro Ikegawa, Amy Pizzino, Johanna L. Schmidt, Genevieve Bernard, Raphael Schiffmann, Marjo S. van der Knaap, Cas Simons^*, Ryan J. Taft, Adeline Vanderver

^*Corresponding author for this work

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

Abstract

Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.

Original language	English
Pages (from-to)	144-152
Number of pages	9
Journal	Annals of Clinical and Translational Neurology
Volume	7
Issue number	1
Early online date	7 Jan 2020
DOIs	https://doi.org/10.1002/acn3.50957
Publication status	Published - Jan 2020

Funding

We thank the patients and their families. AP, JLS, AT, and AV are supported by the Myelin Disorders Bioregistry Project. GB has received the New Investigator Salary Award from the Canadian Institutes of Health Research (2017‐2022). Sequencing was provided by Illumina, Inc. The Myelin Disorders Bioregistry Project was supported by the Children's Research Institute at the Children's Hospital of Philadelphia. This study was in part financed by the Australian National Health and Medical Research Council (NHMRC 1068278). The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. We thank Elizabeth Bhoj and Yanick J. Crow for their consultation and work with regard to cases undergoing genome sequencing. We also thank Brian P. Brooks, Sara Zondag, Lisa Green, Sudeshna Mitra, Lucy Civitello, Natasha Shur, Valeria Zincke, Silvia Delgado, Janice E. Brunstrom‐Hernandez, Celia Chang, Robert Keating, Jessica Carpenter, Jayne Antony, Shekeeb Mohammad, Marc C. Patterson, Tarannum Lateef, Taeun Chang, James Reese, Shaaron Towns, Diego Preciado, Dewi Depositario‐Cabacar, Meganne Leach, Catherine Zorc, Jenny Wilson, Eileen Walters, Steven Leber, Srikanth Muppidi, Kimberly Chapman, Amy Waldman, Lindsey Scussel, Andrea Gropman, Tena Rosser, Phillip Pearl, Eva Fung, Sumit Parikh, Bruce Cohen, James Reggin, Cengiz Yalcinkaya, Yuval Shafrir, Mark DiFazio, Emily Freilich, Charles Lourenco, Carolina Tesi‐Rocha, Brent Fogel, Jay Desai, Hernan Amartino, Nicole Weaver, Valynne Long, Michael Gambello, Melissa Cirillo, Ilana Kahn, Deepak Gill, Maria Gieron, Emily de Los Reyes, Bennet Lavenstein, Brendan Lanpher, Gerhard Kurleman, Dan Miller, Amirah Khouzam, Vani Rajan, Erin Ramos, Shimul Chowdhury, Tina Hambuch, Kelin Ru, Greg Baillie, Sean Grimmond, Ljuba Caldovic, Joe Devaney Miriam Bloom, Sarah Evans, Jennifer Murphy, and Nathan McNeill for providing care to the affected individuals and families, referral to the Myelin Disorders Bioregistry Project, or previous contributions to this longstanding project. BRL, ED, AG, VG, and RJT are/were employees of Illumina, Inc. Nemours receives revenue from diagnostic testing performed in the Nemours Molecular Diagnostics Laboratory. GB has received compensation for traveling to meetings and advisory boards from Ionis, Shire/Takeda, Actelion Pharmaceuticals and Children's Hospital of Philadelphia. She served on the scientific advisory board for Ionis (2019) and has received research grants from Shire/Takeda and Bluebird Bio. AV receives support from Shire, Gilead, Eli Lilly and Illumina for research activities. Otherwise the authors report no conflict of interest.

Funders	Funder number
Myelin Disorders Bioregistry Project
Murdoch Children's Research Institute
Eli Lilly and Illumina
Victorian Government's
Gilead Sciences
Operational Infrastructure Support Program
Children's Hospital of Philadelphia
Shire Australia
Canadian Institutes of Health Research	2017‐2022
National Health and Medical Research Council	NHMRC 1068278, 1068278

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Helman, G., Lajoie, B. R., Crawford, J., Takanohashi, A., Walkiewicz, M., Dolzhenko, E., Gross, A. M., Gainullin, V. G., Bent, S. J., Jenkinson, E. M., Ferdinandusse, S., Waterham, H. R., Dorboz, I., Bertini, E., Miyake, N., Wolf, N. I., Abbink, T. E. M., Kirwin, S. M., Tan, C. M., ... Vanderver, A. (2020). Genome sequencing in persistently unsolved white matter disorders. Annals of Clinical and Translational Neurology, 7(1), 144-152. https://doi.org/10.1002/acn3.50957

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abstract = "Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64\% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85\% in this retrospective cohort.",

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Helman, G, Lajoie, BR, Crawford, J, Takanohashi, A, Walkiewicz, M, Dolzhenko, E, Gross, AM, Gainullin, VG, Bent, SJ, Jenkinson, EM, Ferdinandusse, S, Waterham, HR, Dorboz, I, Bertini, E, Miyake, N, Wolf, NI, Abbink, TEM, Kirwin, SM, Tan, CM, Hobson, GM, Guo, L, Ikegawa, S, Pizzino, A, Schmidt, JL, Bernard, G, Schiffmann, R, van der Knaap, MS, Simons, C, Taft, RJ & Vanderver, A 2020, 'Genome sequencing in persistently unsolved white matter disorders', Annals of Clinical and Translational Neurology, vol. 7, no. 1, pp. 144-152. https://doi.org/10.1002/acn3.50957

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AU - Gross, Andrew M.

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Genome sequencing in persistently unsolved white matter disorders

Abstract

Funding

UN SDGs

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