Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations

Crook, Ashley; Williams, Kelly L.; Adams, Lorel; Blair, Ian P.; Rowe, Dominic B.

doi:10.1080/21678421.2017.1332079

Cited by 27 publications

(53 citation statements)

References 109 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 1 , 21 – 25 Pathogenic mutations in other genes including FUS, CHCHD10, CCNF, UBQLN2, SQSTM1 , and VCP have also been found in patients with ALS-FTD. 26 However, the genetic etiology of quite a few patients with ALS-FTD remains unclear.…”

Section: Discussionmentioning

confidence: 99%

ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia

Zhang

Liu

et al. 2018

Neurol Genet

View full text Add to dashboard Cite

ObjectiveTo investigate the genetic contribution of ANXA11, a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia.MethodsSequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR.ResultsWe identified 6 nonsynonymous heterozygous mutations (5 novel and 1 recurrent), 1 splice site mutation, and 1 deletion of 10 amino acids (not accounted in the mutant frequency) in 11 unrelated patients, accounting for a mutant frequency of 5.6% (1/18) in FALS, 2.3% (8/353) in SALS, and 8.3% (1/12) in ALS-FTD. The deletion of 10 amino acids was detected in 1 clinically undetermined male with an ALS family history who had atrophy in hand muscles and myotonic discharges revealed by EMG. The novel p. P36R mutation was identified in 1 FALS index, 1 patient with SALS, and 1 ALS-FTD. The splicing mutation (c.174-2A>G) caused in-frame skipping of the entire exon 6. The rest missense mutations including p.D40G, p.V128M, p.S229R, p.R302C and p.G491R were found in 6 unrelated patients with SALS.ConclusionsThe ANXA11 gene is one of the most frequently mutated genes in Chinese patients with SALS. A canonical splice site mutation leading to skipping of the entire exon 6 further supports the loss-of-function mechanism. In addition, the study findings further expand the ANXA11 phenotype, first highlighting its pathogenic role in ALS-FTD.

show abstract

Section: Discussionmentioning

confidence: 99%

ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia

Zhang

Liu

et al. 2018

Neurol Genet

View full text Add to dashboard Cite

show abstract

“…In addition to incomplete penetrance, incorrect classification of sporadic ALS cases may arise from inadequate knowledge or reporting of family history and may be masked, for example, by the death of at-risk family members from other causes prior to ALS onset 6 , 30 . Not recognising a familial basis of disease can have significant genetic counselling implications for immediate family members 6 , 30 whose risk of developing ALS greatly increases. Correct classification of familial and sporadic cases allows health professionals to make appropriate recommendations regarding genetic testing and counselling of ALS patients and their families.…”

Section: Discussionmentioning

confidence: 99%

Identity by descent analysis identifies founder events and links SOD1 familial and sporadic ALS cases

et al. 2020

Self Cite

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by the loss of upper and lower motor neurons resulting in paralysis and eventual death. Approximately 10% of ALS cases have a family history of disease, while the remainder present as apparently sporadic cases. Heritability studies suggest a significant genetic component to sporadic ALS, and although most sporadic cases have an unknown genetic aetiology, some familial ALS mutations have also been found in sporadic cases. This suggests that some sporadic cases may be unrecognised familial cases with reduced disease penetrance in their ancestors. A powerful strategy to uncover a familial link is identity-by-descent (IBD) analysis, which detects genomic regions that have been inherited from a common ancestor. IBD analysis was performed on 83 Australian familial ALS cases from 25 families and three sporadic ALS cases, each of whom carried one of three SOD1 mutations (p.I114T, p.V149G and p.E101G). We defined five unique 350-SNP haplotypes that carry these mutations in our cohort, indicative of five founder events. This included two founder haplotypes that carry SOD1 p.I114T; linking familial and sporadic cases. We found that SOD1 p.E101G arose independently in each family that carries this mutation and linked two families that carry SOD1 p.V149G. The age of disease onset varied between cases that carried each SOD1 p.I114T haplotype. Linking families with identical ALS mutations allows for larger sample sizes and increased statistical power to identify putative phenotypic modifiers.

show abstract

“…Moreover, genetic testing may directly benefit those undergoing it by empowering and helping them in life decisions, and lifestyle, health and procreation choices. Additionally, many individuals consider the anxiety of living with the unknown as worse than knowing whether or not to be at genetic risk 61‐63 …”

Section: Discussionmentioning

confidence: 99%

The NGS technology for the identification of genes associated with the ALS. A systematic review

Pecoraro

Mandrioli

Carone

et al. 2020

Eur J Clin Investigation

View full text Add to dashboard Cite

Background: More than 30 causative genes have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). The next-generation sequencing (NGS) is a powerful and groundbreaking tool to identify disease-associated variants. Despite documented advantages of NGS, its diagnostic reliability needs to be addressed in order to use this technology for specific routine diagnosis. Material and Methods: Literature database was explored to identify studies comparing NGS and Sanger sequencing for the detection of variants causing ALS. We collected data about patients' characteristics, disease type and duration, NGS and Sanger properties. Results: More than 200 bibliographic references were identified, of which only 14 studies matching our inclusion criteria. Only 2 out of 14 studies compared results of NGS analysis with the Sanger sequencing. Twelve studies screened causative genes associated to ALS using NGS technologies and confirmed the identified variants with Sanger sequencing. Overall, data about more 2,000 patients were analysed. The number of genes that were investigated in each study ranged from 1 to 32, the most frequent being FUS, OPTN, SETX and VCP. NGS identified already known mutations in 21 genes, and new or rare variants in 27 genes. Conclusions: NGS seems to be a promising tool for the diagnosis of ALS in routine clinical practice. Its advantages are represented by an increased speed and a lowest sequencing cost, but patients' counselling could be problematic due to the discovery of frequent variants of unknown significance. K E Y W O R D S amyothrophic lateral sclerosis, evidence, gene detection, next-generation sequencing, systematic review 2 of 16 | PECORARO Et Al. 4 of 16 | PECORARO Et Al.duration, site of onset); (d) characteristics of NGS technologies; (e) investigated outcomes as defined above.

show abstract

Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations

Cited by 27 publications

References 109 publications

ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia

ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia

Identity by descent analysis identifies founder events and links SOD1 familial and sporadic ALS cases

The NGS technology for the identification of genes associated with the ALS. A systematic review

Contact Info

Product

Resources

About