Genetics at the heart of advances in HSP

Posted - February 2021 in Living with HSP - Management & Treatment News

Continuous technological innovation the key

 

Here are two Australian papers on genetics in neuromuscular diseases, the first from WA reflecting broadly on established and emerging technological innovations in the field; and the second from Victoria reporting on the benefits from new approaches to securing the genetics diagnosis.

 


 

Enormous gains with modern gene testing

Many more advances possible

Abstract

The impact of high-throughput sequencing in genetic neuromuscular disorders cannot be overstated. The ability to rapidly and affordably sequence multiple genes simultaneously has enabled a second golden age of Mendelian disease gene discovery, with flow-on impacts for rapid genetic diagnosis, evidence-based treatment, tailored therapy development, carrier-screening, and prevention of disease recurrence in families.

However, there are likely many more neuromuscular disease genes and mechanisms to be discovered. Many patients and families remain without a molecular diagnosis following targeted panel sequencing, clinical exome sequencing, or even genome sequencing.

Here we review how massively parallel, or next-generation, sequencing has changed the field of genetic neuromuscular disorders, and anticipate future benefits of recent technological innovations such as RNA-seq implementation and detection of tandem repeat expansions from short-read sequencing.

SOURCE: Mol Diagn Ther. 2020 Dec;24(6):641-652. doi: 10.1007/s40291-020-00495-2. Epub 2020 Sep 30. PMID: 32997275

The Impact of Next-Generation Sequencing on the Diagnosis, Treatment, and Prevention of Hereditary Neuromuscular Disorders

Sarah J Beecroft 1 2Phillipa J Lamont 3Samantha Edwards 1 2Hayley Goullée 1 2Mark R Davis 4Nigel G Laing 1 2 3Gianina Ravenscroft 5 6

1 Neurogenetic Diseases Group, Centre for Medical Research, QEII Medical Centre, University of Western Australia, 6 Verdun St, Nedlands, WA, 6009, Australia.

2 Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, 6009, Australia.

3 Neurogenetic Clinic, Royal Perth Hospital, Perth, Australia.

4 Neurogenetic Unit, Department of Diagnostic Genomics, PP Block, QEII Medical Centre, Nedlands, WA, Australia.

5 Neurogenetic Diseases Group, Centre for Medical Research, QEII Medical Centre, University of Western Australia, 6 Verdun St, Nedlands, WA, 6009, Australia.

6 Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, WA, 6009, Australia.

 


 

Better HSP detection and management

Exome sequencing & bioinformatics analysis are key

In this study, 40% of people with HSP (10/25) received a genetic diagnosis that would not have been possible by more standard means. Overall, the genetic findings had impacts on disease management in 68% of participants.

This Australian study demonstrates the value of a combined exome sequencing and bioinformatics analysis approach to detection and management of a range of neurological disorders including HSP.

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. 

SOURCE: J Neurol Sci. 2021 Jan 15;420:117260.  doi: 10.1016/j.jns.2020.117260. Epub 2020 Dec 3. PMID: 33310205 Copyright © 2020 Elsevier B.V. All rights reserved.

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 1Amy Schneider 2Ella Lynch 3Melissa Martyn 4Dennis Velakoulis 5Michael Fahey 6Patrick Kwan 7Richard Leventer 8Haloom Rafehi 9Belinda Chong 10Zornitza Stark 11Sebastian Lunke 10Dean G Phelan 11Melanie O’Keefe 12Kirby Siemering 12Kirsty West 13Adrienne Sexton 14Anna Jarmolowicz 15Jessica A Taylor 14Joshua Schultz 14Rebecca Purvis 14Eloise Uebergang 16Heather Chalinor 17Belinda Creighton 18Nikki Gelfand 19Tamar Saks 20Yael Prawer 19Yana Smagarinsky 21Tianxin Pan 22Ilias Goranitis 23Zanfina Ademi 24Clara Gaff 25Aamira Huq 17Maie Walsh 14Paul A James 14Emma I Krzesinski 26Mathew Wallis 27Chloe A Stutterd 28Melanie Bahlo 9Martin B Delatycki 29Samuel F Berkovic 2

1 Neuropsychiatry, Royal Melbourne Hospital, Melbourne, Australia; Melbourne Neuropsychiatry Centre & Department of Psychiatry, University of Melbourne, Melbourne, Australia; Melbourne Genomics Health Alliance, Melbourne, Australia.

2 Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia.

3 Melbourne Genomics Health Alliance, Melbourne, Australia; Victorian Clinical Genetics Services, Melbourne, Australia.

4 Melbourne Genomics Health Alliance, Melbourne, Australia; Murdoch Children’s Research Institute, Melbourne, Australia.

5 Neuropsychiatry, Royal Melbourne Hospital, Melbourne, Australia; Melbourne Neuropsychiatry Centre & Department of Psychiatry, University of Melbourne, Melbourne, Australia.

6 Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia; Monash Genetics, Monash Health, Melbourne, Australia.

7 Department of Neuroscience, Central Clinical School, Monash University, Alfred Hospital, Melbourne, Australia; Departments of Medicine and Neurology, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.

8 Murdoch Children’s Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

9 Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Australia.

10 Victorian Clinical Genetics Services, Melbourne, Australia; Murdoch Children’s Research Institute, Melbourne, Australia.

11 Victorian Clinical Genetics Services, Melbourne, Australia; Murdoch Children’s Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia

12 Australian Genome Research Facility, Melbourne, Australia.

13 Melbourne Genomics Health Alliance, Melbourne, Australia; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia.

14 Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia.

15 Melbourne Genomics Health Alliance, Melbourne, Australia; Victorian Clinical Genetics Services, Melbourne, Australia; Genomic Medicine, Royal Melbourne Hospital, Melbourne, Australia.

16 Murdoch Children’s Research Institute, Melbourne, Australia.

17 Clinical Genetics, Austin Health, Melbourne, Australia.

18 Melbourne Genomics Health Alliance, Melbourne, Australia; Clinical Genetics, Austin Health, Melbourne, Australia.

19 Monash Genetics, Monash Health, Melbourne, Australia; Department of Paediatrics, Monash University, Melbourne, Australia.

20 Monash Genetics, Monash Health, Melbourne, Australia.

21 Victorian Clinical Genetics Services, Melbourne, Australia.

22 Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.

23 Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia; Australian Genomics Health Alliance, Melbourne, Australia.

24 School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

25 Melbourne Genomics Health Alliance, Melbourne, Australia.

26 Monash Genetics, Monash Health, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia.

27 Clinical Genetics, Austin Health, Melbourne, Australia; School of Medicine, University of Tasmania, Australia.

28 Murdoch Children’s Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Clinical Genetics, Austin Health, Melbourne, Australia.

29 Victorian Clinical Genetics Services, Melbourne, Australia; Clinical Genetics, Austin Health, Melbourne, Australia.

 

 

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