The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

Eratne, Dhamidhu; Schneider, Amy L; Lynch, Ella; Martyn, Melissa; Velakoulis, Dennis; Fahey, Michael; Kwan, Patrick; Leventer, Richard; Rafehi, Haloom; Chong, Belinda; Stark, Zornitza; Lunke, Sebastian; Phelan, Dean G; O'Keefe, Melanie; Siemering, Kirby; West, Kirsty; Sexton, Adrienne; Jarmolowicz, Anna; Taylor, Jessica A; Schultz, Joshua; Purvis, Rebecca; Uebergang, Eloise; Chalinor, Heather; Creighton, Belinda; Gelfand, Nikki; Saks, Tamar; Prawer, Yael; Smagarinsky, Yana; Pan, Tianxin; Goranitis, Ilias; Ademi, Zanfina; Gaff, Clara; Huq, Aamira; Walsh, Maie; James, Paul A; Krzesinski, Emma I; Wallis, Mathew J; Stutterd, Chloe A; Bahlo, Melanie; Delatycki, Martin B; Berkovic, Samuel F

doi:10.1016/j.jns.2020.117260

Title

The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

Publication Date

2021-01-15

Author(s)

Eratne, Dhamidhu

Schneider, Amy L

Lynch, Ella

Martyn, Melissa

Velakoulis, Dennis

Fahey, Michael

Kwan, Patrick

Leventer, Richard

Rafehi, Haloom

Chong, Belinda

Stark, Zornitza

Lunke, Sebastian

Phelan, Dean G

O'Keefe, Melanie

Siemering, Kirby

West, Kirsty

Sexton, Adrienne

Jarmolowicz, Anna

Taylor, Jessica A

Schultz, Joshua

Purvis, Rebecca

Uebergang, Eloise

Chalinor, Heather

Creighton, Belinda

Gelfand, Nikki

Saks, Tamar

Prawer, Yael

Smagarinsky, Yana

Pan, Tianxin

Goranitis, Ilias

Ademi, Zanfina

Gaff, Clara

Huq, Aamira

Walsh, Maie

James, Paul A

Krzesinski, Emma I

Wallis, Mathew J

Stutterd, Chloe A

Bahlo, Melanie

Delatycki, Martin B

Berkovic, Samuel F

Subject

Diagnosis

Neurodegenerative

Neurogenetics

Neurology

Next generation sequencing

Type of document

Journal Article

OrcId

#PLACEHOLDER_PARENT_METADATA_VALUE#

DOI

10.1016/j.jns.2020.117260

Abstract

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.

Link

link

Citation

Journal of the Neurological Sciences 2021; 420: 117260

Jornal Title

Journal of the Neurological Sciences

Austin Health

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