Looking for differences in copy number between blood and brain in sporadic amyotrophic lateral sclerosis

Pamphlett, Roger; Morahan, Julia M.; Luquin, Natasha; Yu, Bing

doi:10.1002/mus.22095

Cited by 18 publications

(16 citation statements)

References 43 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although evidence for an oligogenic mechanism for ALS was present in our present study, we looked only at single nucleotide variants. Other genetic abnormalities, such as copy number variants, DNA methylation 39 , or somatic mutations 40 could interact with the variants we found in our ALS TRIO patients to confer further susceptibility to disease. For example, when 12 of the present ALS TRIO patients had genome-wide CNVs analysed with microarrays in a previous study 40 , de novo CNVs were found in 11 of them ( Table 1 ).…”

Section: Discussionmentioning

confidence: 81%

Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS

Steinberg¹,

Koboldt³

et al. 2015

Sci Rep

Self Cite

View full text Add to dashboard Cite

The contribution of genetic variants to sporadic amyotrophic lateral sclerosis (ALS) remains largely unknown. Either recessive or de novo variants could result in an apparently sporadic occurrence of ALS. In an attempt to find such variants we sequenced the exomes of 44 ALS-unaffected-parents trios. Rare and potentially damaging compound heterozygous variants were found in 27% of ALS patients, homozygous recessive variants in 14% and coding de novo variants in 27%. In 20% of patients more than one of the above variants was present. Genes with recessive variants were enriched in nucleotide binding capacity, ATPase activity, and the dynein heavy chain. Genes with de novo variants were enriched in transcription regulation and cell cycle processes. This trio study indicates that rare private recessive variants could be a mechanism underlying some case of sporadic ALS, and that de novo mutations are also likely to play a part in the disease.

show abstract

Section: Discussionmentioning

confidence: 81%

Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS

Steinberg¹,

Koboldt³

et al. 2015

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since then others have failed to find ALS brain-specific mutations involving either the length of androgen receptor triplet repeats [23], single nucleotide variants of coding and non-coding regions of TARDP [24], [25], or of all exons and the promoter of superoxide dismutase 1 [26]. ALS brain-situated genome-wide variants in chromosomal copy number [27] and in DNA methylation [28] have been reported, but these still require independent validation. Future exome and whole-genome sequencing of different tissues may be needed to reveal what role somatic mutations play in sporadic ALS.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

Self Cite

View full text Add to dashboard Cite

Gene mutations that preferentially affect the CNS have been implicated in a number of neurological disorders. This leads to the possibility that a disease-causing mutation present only in CNS tissues could be missed if it were tested in a blood DNA sample only. The commonest mutation in amyotrophic lateral sclerosis (ALS) is an expansion of the hexanucleotide repeats of C9orf72. To find out if CNS-specific mutations of this gene could cause some cases of ALS we looked for differences in the size of C9orf72 repeats between DNA from the CNS and from white blood cells (WBCs) of 38 sporadic ALS patients, using a repeat-primed PCR screening test. We also looked for differences in C9orf72 repeats in WBC DNA from 6 ALS-discordant and 1 ALS-concordant monozygotic twins. Abnormally expanded C9orf72 repeats were found in 13% of the ALS CNS samples, as well as in their paired WBC DNA. The 87% of ALS CNS samples with normal-sized C9orf72 repeats had the same number of repeats in paired WBC samples. All ALS-discordant twins had the same normal numbers of WBC C9orf72 repeats. Although previous work suggests some tissue mosaicism in C9orf72 repeat size is probably present, this study indicates that this is not likely to be of sufficient magnitude to result in a normal C9orf72 repeat length in blood but an abnormally expanded repeat length in the CNS. This suggests that a blood DNA test alone will usually be sufficient to make a diagnosis of C9orf72 repeat-related ALS.

show abstract

“…Another neurodegenerative disease that has been recently associated with somatic mosaicism is sporadic amyotrophic lateral sclerosis, sometimes called Lou Gehrig's disease. Following tissue-specific analysis of genomic variations, brain-specific CNVs were detected in the majority of patients [114]. Single-gene genomic variations such as trinucleotide repeat expansions are a frequent cause of somatic mosaicism in the diseased brain.…”

Section: Single Cell Genomics Of Neurological and Psychiatric Diseasesmentioning

confidence: 99%

Single Cell Genomics of the Brain: Focus on Neuronal Diversity and Neuropsychiatric Diseases

Iourov¹,

Sg²,

Yurov³

2012

View full text Add to dashboard Cite

Single cell genomics has made increasingly significant contributions to our understanding of the role that somatic genome variations play in human neuronal diversity and brain diseases. Studying intercellular genome and epigenome variations has provided new clues to the delineation of molecular mechanisms that regulate development, function and plasticity of the human central nervous system (CNS). It has been shown that changes of genomic content and epigenetic profiling at single cell level are involved in the pathogenesis of neuropsychiatric diseases (schizophrenia, mental retardation (intellectual/leaning disability), autism, Alzheimer’s disease etc.). Additionally, several brain diseases were found to be associated with genome and chromosome instability (copy number variations, aneuploidy) variably affecting cell populations of the human CNS. The present review focuses on the latest advances of single cell genomics, which have led to a better understanding of molecular mechanisms of neuronal diversity and neuropsychiatric diseases, in the light of dynamically developing fields of systems biology and “omics”.

show abstract

Looking for differences in copy number between blood and brain in sporadic amyotrophic lateral sclerosis

Abstract: Brain-specific CNVs may be common and appear to be present in a proportion of patients with SALS. The more detailed copy number analysis that is becoming available with massively parallel sequencing may uncover brain-specific CNVs that underlie some cases of SALS.

Cited by 18 publications

References 43 publications

Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS

Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS

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

Single Cell Genomics of the Brain: Focus on Neuronal Diversity and Neuropsychiatric Diseases

Contact Info

Product

Resources

About