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 JournalArticleAcademicpeer-review


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 languageEnglish
Pages (from-to)144-152
Number of pages9
JournalAnnals of Clinical and Translational Neurology
Issue number1
Early online date7 Jan 2020
Publication statusPublished - Jan 2020


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