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

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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.

Introduction

Next generation sequencing (NGS) technologies are becoming established in clinical care and are particularly helpful for genetically heterogeneous and phenotypically variable neurological disorders, where there are broad differential diagnoses and diagnostic uncertainty. [4,14] Exome sequencing (ES) has had a major impact on paediatrics and especially paediatric neurological disorders. It is also of high relevance to the practice of adult neurology, given many neurological conditions that present to neurogenetics clinics such as ataxia, dementia and spastic paraparesis, have complex and overlapping clinical features, and often have prolonged and costly ‘diagnostic odysseys’.

Standard NGS pipelines focus only on small insertion and deletions and single nucleotide variants. Methodological advances in bioinformatic pipelines can be applied to further increase diagnostic yield, with a recent example being the development and application of repeat expansion detection methods which can be applied to both ES and genome sequencing (GS). [3,20] Repeat expansions are an important contributor to over 30 neurological disorders, including dementia and ataxias, and are underdiagnosed due to the requirement of a typical clinical presentation to motivate additional and costly genetic testing for repeat expansions.

Furthermore, as most studies investigating the diagnostic yield of ES in a range of neurological disorders have focused on the paediatric population, studies in adult populations are important to demonstrate the latest gains in NGS-aided diagnosis to provide earlier, more accurate diagnosis, improving prognostic and genetic counselling and outcomes for patients and families, delivering precision care and efficiency in healthcare systems, and promoting timely recruitment for clinical trials.

As of August 2020, there is limited, but not secured, funding available in Australia for NGS in adult neurological disorders. The Australian Genomics Health Alliance and Melbourne Genomics Health Alliance([5]; [17]Stark, Boughtwood, et al., 2019) have conducted several flagship studies to study the diagnostic and wider utility of NGS and to demonstrate evidence for government funded genomic sequencing, for example in children, peripheral neuropathy and focal epilepsy. [8,19,22,23] In this study we aimed to study the diagnostic yield and impacts on management of ES, making use of an extended bioinformatics repeat expansion detection pipeline, in common chronic neurological disorders of adolescents and adults recruited from multiple real-world clinical settings in Australia.

Section snippets

Study design and participants

This was a prospective multi-site study designed to assess the utility of ES in the care of patients in the State of Victoria, Australia, with a broad range of neurological phenotypes where there was suspected genetic aetiology: ataxia, dementia, spastic paraplegia, dystonia, motor neuron disease, Parkinson's disease, and complex/unspecified neurological disease (involving pyramidal, extrapyramidal, cerebellar, and/or cognitive features, with or without seizures and extra-neurological

Patient characteristics

We received 247 referrals between August 2017 and October 2018 from a broad range of clinical settings including genetics clinics, public and private neurology and neuropsychiatry services. Forty-one were deemed not eligible after review by the study multidisciplinary team (16 did not meet age criteria, nine had personal or family member previous testing, four were not based in Victoria, and four were referred on to more specific studies for mitochondrial disorders, peripheral neuropathy and

Discussion

In this prospective, multi-site study we utilised ES and an extended bioinformatics repeat expansion pipeline in patients with broad neurological phenotypes from a range of real-world clinical settings. A genetic diagnosis was made in 21% (34/160) of patients. Our findings, with broad and inclusive eligibility criteria and recruitment from a variety of busy clinical services, are comparable to studies in specialist centres that have included diverse neurological phenotypes in adolescents and

Data availability statement

The authors declare that all supporting data are available within the article and its Supplementary Material. Details of individual variants will be entered by the reporting laboratory, VCGS, into the publicly accessible repository, ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). Other individual de-identified patient data will not be available in a publicly accessible repository to protect the interests of the patients and their families.

Declaration of Competing Interest

All the authors have nothing to disclose.

Statistical Analysis conducted by Dr. Dhamidhu Eratne, MD, Melbourne Genomics and Neuropsychiatry, Royal Melbourne Hospital

Acknowledgements

The authors would also like to thank all the referring clinicians, Professor Elsdon Storey and all other clinicians involved in assessments and recruitment at the genetics clinics, Anne Harbison and Rigan Tytherleigh for data entry, and A/Professor Tiong Tan, and scientists and clinicians at the Victorian Clinical Genetics Services. The study was funded by the State Government of Victoria (Department of Health and Human Services) and the ten member organisations of the Melbourne Genomics Health

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