Systematic evaluation of genetic mutations in ALS: a population-based study

Maurizio Grassano^{1

2}, Andrea Calvo^{3

4}, Cristina Moglia^{3

4}, Luca Sbaiz⁵, Maura Brunetti⁵, Marco Barberis⁵, Federico Casale³, Umberto Manera^{3

4}, Rosario Vasta³, Antonio Canosa^{3

4}, Sandra D'Alfonso⁶, Lucia Corrado⁶, Letizia Mazzini⁷, Clifton Dalgard^{8

9}, Ramita Karra², Ruth Chia², Bryan Traynor^#^{2

10

11

12

13}, Adriano Chiò^#^{3

4

14}

Affiliations

¹ Department of Neuroscience, University of Turin, Torino, Italy grassano.maurizio@gmail.com.
² Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, Bethesda, Maryland, USA.
³ Department of Neuroscience, University of Turin, Torino, Italy.
⁴ S.C. Neurologia 1U, Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.
⁵ Laboratory of Genetics, Department of Clinical Pathology, Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.
⁶ Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont Amedeo Avogadro School of Medicine, Novara, Piemonte, Italy.
⁷ Department of Neurology, University Hospital Maggiore della Carità, Novara, Italy.
⁸ Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
⁹ The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
¹⁰ Department of Neurology and Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA.
¹¹ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹² National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
¹³ ASO Rapid Development Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA.
¹⁴ Institute of Cognitive Sciences and Technologies, National Council of Research, Rome, Italy.

^# Contributed equally.

PMID: 35896380
PMCID: PMC9606529
DOI: 10.1136/jnnp-2022-328931

Systematic evaluation of genetic mutations in ALS: a population-based study

Maurizio Grassano et al. J Neurol Neurosurg Psychiatry. 2022.

. 2022 Jul 27;93(11):1190-1193.

doi: 10.1136/jnnp-2022-328931. Online ahead of print.

Authors

Affiliations

¹ Department of Neuroscience, University of Turin, Torino, Italy grassano.maurizio@gmail.com.
² Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, Porter Neuroscience Research Center, National Institute on Aging, Bethesda, Maryland, USA.
³ Department of Neuroscience, University of Turin, Torino, Italy.
⁴ S.C. Neurologia 1U, Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.
⁵ Laboratory of Genetics, Department of Clinical Pathology, Azienda Ospedaliero Universitaria Citta della Salute e della Scienza di Torino, Torino, Italy.
⁶ Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont Amedeo Avogadro School of Medicine, Novara, Piemonte, Italy.
⁷ Department of Neurology, University Hospital Maggiore della Carità, Novara, Italy.
⁸ Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
⁹ The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
¹⁰ Department of Neurology and Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA.
¹¹ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.
¹² National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
¹³ ASO Rapid Development Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, NIH, Rockville, MD, USA.
¹⁴ Institute of Cognitive Sciences and Technologies, National Council of Research, Rome, Italy.

^# Contributed equally.

PMID: 35896380
PMCID: PMC9606529
DOI: 10.1136/jnnp-2022-328931

Abstract

Background: A genetic diagnosis in Amyotrophic Lateral Sclerosis (ALS) can inform genetic counselling, prognosis and, in the light of incoming gene-targeted therapy, management. However, conventional genetic testing strategies are often costly and time-consuming.

Objective: To evaluate the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic genetic test for ALS.

Methods: In this population-based cohort study, 1043 ALS patients from the Piemonte and Valle d'Aosta Register for ALS and 755 healthy individuals were screened by WGS for variants in 42 ALS-related genes and for repeated-expansions in C9orf72 and ATXN2.

Results: A total of 279 ALS cases (26.9%) received a genetic diagnosis, namely 75.2% of patients with a family history of ALS and 21.5% of sporadic cases. The mutation rate among early-onset ALS patients was 43.9%, compared with 19.7% of late-onset patients. An additional 14.6% of the cohort carried a genetic factor that worsen prognosis.

Conclusions: Our results suggest that, because of its high diagnostic yield and increasingly competitive costs, along with the possibility of retrospectively reassessing newly described genes, WGS should be considered as standard genetic testing for all ALS patients. Additionally, our results provide a detailed picture of the genetic basis of ALS in the general population.

Keywords: ALS; C9ORF; GENETICS; MOTOR NEURON DISEASE; NEUROGENETICS.

PubMed Disclaimer

Conflict of interest statement

Competing interests: MG, CM, LS, MBr, MBa, FC, UM, RV, AC, SD'A, LC, LM, CD, RK and RC report no disclosures. AC has received research grant from Cytokinetics. BT holds European, Canadian and American patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. AC serves on scientific advisory boards for Mitsubishi Tanabe, Roche and Cytokinetics, and has received a research grant from Italfarmaco.

Figures

**Figure 1**
Distribution of mutated genes across our cohort. (A) The frequency of mutations in all ALS cases (out band), sporadic cases (middle band) and familial cases (inner circle). (B) The number of potentially pathogenic variants identified per gene. ALS, Amyotrophic Lateral Sclerosis

See this image and copyright information in PMC

References

1. Chia R, Chiò A, Traynor BJ. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol 2018;17:94–102. 10.1016/S1474-4422(17)30401-5 - DOI - PMC - PubMed
1. Shepheard SR, Parker MD, Cooper-Knock J, et al. . Value of systematic genetic screening of patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2021;92:510–8. 10.1136/jnnp-2020-325014 - DOI - PMC - PubMed
1. Logroscino G, Marin B, Piccininni M, et al. . Referral bias in ALS epidemiological studies. PLoS One 2018;13:e0195821. 10.1371/journal.pone.0195821 - DOI - PMC - PubMed
1. Grassano M, Calvo A, Moglia C. Mutational analysis of known ALS genes in an Italian population-based cohort. Neurology 2020. 10.1212/WNL.0000000000011209 - DOI - PMC - PubMed
1. Chia R, Sabir MS, Bandres-Ciga S, et al. . Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet 2021;53:294–303. 10.1038/s41588-021-00785-3 - DOI - PMC - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
- PubMed Central

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Systematic evaluation of genetic mutations in ALS: a population-based study

Affiliations

Systematic evaluation of genetic mutations in ALS: a population-based study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources