Systematic evaluation of genetic mutations in ALS: a population-based study.
ALS
C9ORF
GENETICS
MOTOR NEURON DISEASE
NEUROGENETICS
Journal
Journal of neurology, neurosurgery, and psychiatry
ISSN: 1468-330X
Titre abrégé: J Neurol Neurosurg Psychiatry
Pays: England
ID NLM: 2985191R
Informations de publication
Date de publication:
27 Jul 2022
27 Jul 2022
Historique:
received:
23
01
2022
accepted:
22
04
2022
entrez:
27
7
2022
pubmed:
28
7
2022
medline:
28
7
2022
Statut:
aheadofprint
Résumé
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. To evaluate the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic genetic test for ALS. 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. 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. 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
To evaluate the diagnostic yield and advantages of whole-genome sequencing (WGS) as a standard diagnostic genetic test for ALS.
METHODS
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
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
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.
Identifiants
pubmed: 35896380
pii: jnnp-2022-328931
doi: 10.1136/jnnp-2022-328931
pmc: PMC9606529
mid: NIHMS1822688
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Intramural NIH HHS
ID : ZIA AG000933
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
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.
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