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

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

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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.

Original languageEnglish
Article number117260
Number of pages8
JournalJournal of the Neurological Sciences
Publication statusPublished - 15 Jan 2021


  • Next generation sequencing
  • Neurogenetics
  • Neurology
  • Neurodegenerative
  • Diagnosis

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