Genetic testing in motor neurone disease

Dharmadasa, Thanuja; Scaber, Jakub; Edmond, Evan C; Marsden, Rachael; Thompson, Alexander G.; Talbot, Kevin; Turner, Martin R

doi:10.1136/practneurol-2021-002989

Cited by 21 publications

(37 citation statements)

References 52 publications

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“…The clinician should also know when diagnostic genetic testing is not indicated. For example, gene testing should not be used for the diagnosis of ALS ( 27 ), which should instead be based on clinical criteria ( 32 ). This is due to the complex and not fully characterized contribution of genetics to the development of ALS ( 27 ).…”

Section: Determining If a Genetic Test Is Indicatedmentioning

confidence: 99%

“…For example, gene testing should not be used for the diagnosis of ALS ( 27 ), which should instead be based on clinical criteria ( 32 ). This is due to the complex and not fully characterized contribution of genetics to the development of ALS ( 27 ). One of the reasons genetic testing can be done in ALS is for the purpose of identifying the causative variant for predictive testing in other family members.…”

Section: Determining If a Genetic Test Is Indicatedmentioning

confidence: 99%

See 1 more Smart Citation

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review

Chin²,

Chin³

et al. 2022

Front. Neurol.

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The diagnosis of inherited neuromuscular disorders is challenging due to their genetic and phenotypic variability. Traditionally, neurophysiology and histopathology were primarily used in the initial diagnostic approach to these conditions. Sanger sequencing for molecular diagnosis was less frequently utilized as its application was a time-consuming and cost-intensive process. The advent and accessibility of next-generation sequencing (NGS) has revolutionized the evaluation process of genetically heterogenous neuromuscular disorders. Current NGS diagnostic testing approaches include gene panels, whole exome sequencing (WES), and whole genome sequencing (WGS). Gene panels are often the most widely used, being more accessible due to availability and affordability. In this mini-review, we describe the benefits and risks of clinical genetic testing. We also discuss the utility, benefits, challenges, and limitations of using gene panels in the evaluation of neuromuscular disorders.

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Section: Determining If a Genetic Test Is Indicatedmentioning

confidence: 99%

Section: Determining If a Genetic Test Is Indicatedmentioning

confidence: 99%

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review

Chin²,

Chin³

et al. 2022

Front. Neurol.

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“…It must also be noted that some gene mutations causing familial MNDs are linked with low penetrance, since some obligatory carriers do not manifest the disease and escape from identification and family pedigree design (e.g., in some cases related to the expansion of the G 4 C 2 repeat present in the C9ORF72 gene) [ 40 , 41 , 42 ]. Several of these forms are classified as sporadic MNDs, and when the corresponding mutations are not fully penetrant, these genes may be either considered causative or disease modifiers for MNDs [ 43 ].…”

Section: Sources and Mechanisms Of Protein Misfolding In Mndsmentioning

confidence: 99%

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

Tedesco

Ferrari

Cozzi

et al. 2022

IJMS

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Motoneuron diseases (MNDs) are neurodegenerative conditions associated with death of upper and/or lower motoneurons (MNs). Proteostasis alteration is a pathogenic mechanism involved in many MNDs and is due to the excessive presence of misfolded and aggregated proteins. Protein misfolding may be the product of gene mutations, or due to defects in the translation process, or to stress agents; all these conditions may alter the native conformation of proteins making them prone to aggregate. Alternatively, mutations in members of the protein quality control (PQC) system may determine a loss of function of the proteostasis network. This causes an impairment in the capability to handle and remove aberrant or damaged proteins. The PQC system consists of the degradative pathways, which are the autophagy and the proteasome, and a network of chaperones and co-chaperones. Among these components, Heat Shock Protein 70 represents the main factor in substrate triage to folding, refolding, or degradation, and it is assisted in this task by a subclass of the chaperone network, the small heat shock protein (sHSPs/HSPBs) family. HSPBs take part in proteostasis by bridging misfolded and aggregated proteins to the HSP70 machinery and to the degradative pathways, facilitating refolding or clearance of the potentially toxic proteins. Because of its activity against proteostasis alteration, the chaperone system plays a relevant role in the protection against proteotoxicity in MNDs. Here, we discuss the role of HSPBs in MNDs and which HSPBs may represent a valid target for therapeutic purposes.

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“…Due to the large amount of heterogeneity in clinical presentation, disease progression and prognosis, and the frequent presence of additional clinical features not related to the motor system, such as frontal temporal dementia (FTD) among ALS patients, misdiagnosis in early ALS onset is common (5, 6). However, genetic testing can end the diagnostic odyssey many patients experience, and there is particular interest in genetic testing due to the increasing number of clinical trials enrolling specific genetic populations (7). Ongoing trials include those for symptomatic ALS patients carrying pathogenic variants in ATXN2, C9orf72, FUS , and SOD1 (NCT04494256, NCT03626012, NCT04931862, NCT04768972, NCT02623699, NCT05039099) (8).…”

Section: Introductionmentioning

confidence: 99%

Clinical testing panels for ALS: global distribution, consistency, and challenges

Dilliott

Nasser

Elnageeb

et al. 2022

Preprint

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Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.

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Genetic testing in motor neurone disease

Cited by 21 publications

References 52 publications

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review

Using gene panels in the diagnosis of neuromuscular disorders: A mini-review

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

Clinical testing panels for ALS: global distribution, consistency, and challenges

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