Annals of Clinical and Translational Neurology (Jan 2020)
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 derKnaap,
- Cas Simons,
- Ryan J. Taft,
- Adeline Vanderver
Affiliations
- Guy Helman
- Murdoch Children's Research Institute The Royal Children's Hospital Melbourne Parkville, Melbourne Australia
- Bryan R. Lajoie
- Illumina Inc. San Diego California
- Joanna Crawford
- Institute for Molecular Bioscience The University of Queensland Brisbane Australia
- Asako Takanohashi
- Division of Neurology Children’s Hospital of Philadelphia Philadelphia Pennsylvania
- Marzena Walkiewicz
- Murdoch Children's Research Institute The Royal Children's Hospital Melbourne Parkville, Melbourne Australia
- Egor Dolzhenko
- Illumina Inc. San Diego California
- Andrew M. Gross
- Illumina Inc. San Diego California
- Vladimir G. Gainullin
- Illumina Inc. San Diego California
- Stephen J. Bent
- Data61 Commonwealth Scientific and Industrial Research Organisation Brisbane Australia
- Emma M. Jenkinson
- Faculty of Biology, Medicine and Health School of Biological Sciences Division of Evolution and Genomic Sciences University of Manchester Manchester United Kingdom
- Sacha Ferdinandusse
- Laboratory Genetic Metabolic Diseases Department of Clinical Chemistry Amsterdam University Medical Centers University of Amsterdam Amsterdam The Netherlands
- Hans R. Waterham
- Laboratory Genetic Metabolic Diseases Department of Clinical Chemistry Amsterdam University Medical Centers University of Amsterdam Amsterdam The Netherlands
- Imen Dorboz
- INSERM UMR 1141 DHU PROTECT Université Paris Diderot‐ Sorbonne Paris Cité France
- Enrico Bertini
- Unit of Neuromuscular and Neurodegenerative Disorders Laboratory of Molecular Medicine Bambino Gesu' Children's Hospital Rome Italy
- Noriko Miyake
- Department of Human Genetics Yokohama City University Graduate School of Medicine Fukuura, Kanazawa‐ku Yokohama 236‐0004Japan
- Nicole I. Wolf
- Department of Child Neurology Emma Children’s Hospital Amsterdam University Medical Centers Vrije Universiteit Amsterdam and Amsterdam Neuroscience Amsterdam The Netherlands
- Truus E. M. Abbink
- Department of Child Neurology Emma Children’s Hospital Amsterdam University Medical Centers Vrije Universiteit Amsterdam and Amsterdam Neuroscience Amsterdam The Netherlands
- Susan M. Kirwin
- Molecular Diagnostics Laboratory Nemours Biomedical Research Nemours/Alfred I. duPont Hospital for Children Wilmington Delaware
- Christina M. Tan
- Molecular Diagnostics Laboratory Nemours Biomedical Research Nemours/Alfred I. duPont Hospital for Children Wilmington Delaware
- Grace M. Hobson
- Molecular Diagnostics Laboratory Nemours Biomedical Research Nemours/Alfred I. duPont Hospital for Children Wilmington Delaware
- Long Guo
- Laboratory of Bone and Joint Diseases RIKEN Center for Integrative Medical Sciences Tokyo Japan
- Shiro Ikegawa
- Laboratory of Bone and Joint Diseases RIKEN Center for Integrative Medical Sciences Tokyo Japan
- Amy Pizzino
- Division of Neurology Children’s Hospital of Philadelphia Philadelphia Pennsylvania
- Johanna L. Schmidt
- Division of Neurology Children’s Hospital of Philadelphia Philadelphia Pennsylvania
- Genevieve Bernard
- Departments of Neurology and Neurosurgery, Pediatrics, and Human Genetics McGill University Montreal Canada
- Raphael Schiffmann
- Institute of Metabolic Disease Baylor Scott & White Research Institute Dallas Texas
- Marjo S. van derKnaap
- Department of Child Neurology Emma Children’s Hospital Amsterdam University Medical Centers Vrije Universiteit Amsterdam and Amsterdam Neuroscience Amsterdam The Netherlands
- Cas Simons
- Murdoch Children's Research Institute The Royal Children's Hospital Melbourne Parkville, Melbourne Australia
- Ryan J. Taft
- Illumina Inc. San Diego California
- Adeline Vanderver
- Division of Neurology Children’s Hospital of Philadelphia Philadelphia Pennsylvania
- DOI
- https://doi.org/10.1002/acn3.50957
- Journal volume & issue
-
Vol. 7,
no. 1
pp. 144 – 152
Abstract
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.
