Can ALS-Associated C9orf72 Repeat Expansions Be Diagnosed on a Blood DNA Test Alone?

Pamphlett, Roger; Cheong, Pak Leng; Trent, Ronald J.; Yu, Bing

doi:10.1371/journal.pone.0070007

Cited by 19 publications

(16 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sporadic cases could be due to de novo somatic expansions from an allele with a normal repeat length, in which case testing of PBL might not reveal the expansion if it was limited to the brain, or ectoderm. However, repeats sizes up to 15 appear stable [144], consistent with an earlier suggestion that pathogenic mosaicism may not arise from a truly normal allele [146].…”

Section: Somatic Mutations As a Mediator Or Modifier In Inherited Neusupporting

confidence: 87%

Review: Somatic mutations in neurodegeneration

Leija‐Salazar

Piette

Proukakis

2018

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

Somatic mutations are postzygotic mutations which may lead to mosaicism, the presence of cells with genetic differences in an organism. Their role in cancer is well established, but detailed investigation in health and other diseases has only been recently possible. This has been empowered by the improvements of sequencing techniques, including single‐cell sequencing, which can still be error‐prone but is rapidly improving. Mosaicism appears relatively common in the human body, including the normal brain, probably arising in early development, but also potentially during ageing. In this review, we first discuss theoretical considerations and current evidence relevant to somatic mutations in the brain. We present a framework to explain how they may be integrated with current views on neurodegeneration, focusing mainly on sporadic late‐onset neurodegenerative diseases (Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis). We review the relevant studies so far, with the first evidence emerging in Alzheimer's in particular. We also discuss the role of mosaicism in inherited neurodegenerative disorders, particularly somatic instability of tandem repeats. We summarize existing views and data to present a model whereby the time of origin and spatial distribution of relevant somatic mutations, combined with any additional risk factors, may partly determine the development and onset age of sporadic neurodegenerative diseases.

show abstract

Section: Somatic Mutations As a Mediator Or Modifier In Inherited Neusupporting

confidence: 87%

Review: Somatic mutations in neurodegeneration

Leija‐Salazar

Piette

Proukakis

2018

Neuropathology Appl Neurobio

View full text Add to dashboard Cite

show abstract

“…Consistent with this, none of the twins harboured an expanded repeat at the C9orf72 locus [21]. 89 Furthermore, previous whole genome sequencing failed to detect any other significant genetic 90 variation between these co-twins; no pathogenic point mutation, insertion/deletion, or structural 91 alteration was identified in the affected twins when compared with their unaffected co-twin [22].…”

Section: Monozygotic Twins Discordant For Als Show No Evidence Of Germentioning

confidence: 53%

Monozygotic twin pairs discordant for amyotrophic lateral sclerosis carry both common and unique epigenetic differences relevant to disease

Young

Kum

Buckland

et al. 2016

Preprint

Self Cite

View full text Add to dashboard Cite

19Amyotrophic lateral sclerosis (ALS) is a devastating late-onset neurodegenerative disorder in 20 which only a small proportion of patients carry an identifiable causative genetic lesion. Despite 21 high heritability estimates, a genetic etiology for most sporadic ALS remains elusive. Here we 22 report the epigenetic profiling of five monozygotic twin pairs discordant for ALS in whom 23 previous genome sequencing excluded a genetic basis for their disease discordance. By studying 24 cytosine methylation patterns in peripheral blood DNA we identified thousands of large 25 between-twin differences at individual CpGs. While the specific sites of difference were largely 26 idiosyncratic to a twin pair, a proportion (involving GABA signalling) were common to all 27 affected individuals. In both instances the differences occurred within genes and pathways 28 related to neurobiological function and dysfunction. Our findings reveal widespread changes in 29 epigenetic marks in ALS patients, consistent with an epigenetic contribution to disease. These 30 findings may be exploited to develop blood-based biomarkers of ALS and develop further 31 insight into disease pathogenesis. We expect that our findings will provide a useful point of 32 reference for further large-scale studies of sporadic ALS. 33

show abstract

“…However, in a larger series, intermediate alleles were identified in control individuals [1,2,85] and were not associated with the age of onset or an increased disease risk for ALS [85], FTD [70,85], or ALS-FTD [85]. Furthermore, in contrast to carriers of large repeat expansions, intermediate-allele carriers are usually somatically stable [29, 84,95], suggesting that alleles in the intermediate range are not pathogenic. In contrast, alleles in the atypical range, similar to large repeat expansion alleles [35,86,96,97], are associated with decreased gene expression [71].…”

Section: Discussionmentioning

confidence: 99%

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

et al. 2018

View full text Add to dashboard Cite

Background: European studies identified the C9orf72 repeat expansion as the most frequent genetic alteration in patients with Huntington disease (HD)-like phenotypes but negative HD genetic testing. Objective: To investigate C9orf72 repeat expansion frequency in individuals tested for HD in a North American tertiary referral laboratory. Methods: Three hundred and seventy-three cases (115 positive and 258 negative for HD) were evaluated by genotyping PCR, with follow-up Southern blot and 5′ repeat methylation status assessment by combined repeat-primed and methylation-specific PCR in a subset. Results: Three cases (all HD-negative) tested positive: 2 had > 2,000 repeats and were methylated, 1 had 80–100 repeats and was unmethylated. Two cases (1 HD-positive and 1 HD-negative) had intermediate alleles (20–29 repeats) and were unmethylated. The remaining 368 cases were negative (< 20 repeats). C9orf72 repeat expansion was absent in patients with HD and was identified in a small subset (1.2%) of patients with negative HD genetic testing. Conclusion: These findings suggest that C9orf72 repeat expansion does not coexist with HTT repeat expansion and that C9orf72 repeat expansion testing is unnecessary for patients with HD. In addition, C9orf72 evaluation may be considered for individuals negative for HD genetic testing. Similar to in previous studies, methylation of C9orf72 repeat expansion was limited to large expansions.

show abstract

Can ALS-Associated C9orf72 Repeat Expansions Be Diagnosed on a Blood DNA Test Alone?

Cited by 19 publications

References 32 publications

Review: Somatic mutations in neurodegeneration

Review: Somatic mutations in neurodegeneration

Monozygotic twin pairs discordant for amyotrophic lateral sclerosis carry both common and unique epigenetic differences relevant to disease

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

Contact Info

Product

Resources

About