Author
Yevgeniya Abramzon
Other affiliations: UCL Institute of Neurology, University College London
Bio: Yevgeniya Abramzon is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Amyotrophic lateral sclerosis & Exome sequencing. The author has an hindex of 19, co-authored 30 publications receiving 7604 citations. Previous affiliations of Yevgeniya Abramzon include UCL Institute of Neurology & University College London.
Papers
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National Institutes of Health1, Cardiff University2, VU University Amsterdam3, Erasmus University Rotterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Johns Hopkins University9, Georgetown University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
3,784 citations
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University of Modena and Reggio Emilia1, Emory University2, University of Pennsylvania3, National Institutes of Health4, University College London5, Johns Hopkins University6, The Catholic University of America7, University of Turin8, Seconda Università degli Studi di Napoli9, University of Siena10, University of Palermo11, University of Cagliari12, Georgetown University13
TL;DR: Exome sequencing data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neurons degeneration.
1,040 citations
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National Institutes of Health1, University College London2, Erasmus University Rotterdam3, VU University Amsterdam4, Cardiff University5, University of Manchester6, University of Turin7, University of Würzburg8, University of Sydney9, University of Birmingham10, University Hospitals Birmingham NHS Foundation Trust11, John Radcliffe Hospital12, The Catholic University of America13, University of Siena14, Lund University15, University of Cagliari16, Oulu University Hospital17, Helsinki University Central Hospital18, University of Pennsylvania19, Tel Aviv Sourasky Medical Center20, Chang Gung University21, Memorial Hospital of South Bend22, University of Tokyo23, Pierre-and-Marie-Curie University24, Centre national de la recherche scientifique25, French Institute of Health and Medical Research26, University of Sheffield27, University Hospital of Wales28, Aneurin Bevan University Health Board29, Johns Hopkins University30
TL;DR: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD, suggesting a one-off expansion occurring about 1500 years ago.
Abstract: Background
We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Methods
We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.
Findings
In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.
Interpretation
A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
Funding
Full funding sources listed at end of paper (see Acknowledgments).
951 citations
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TL;DR: The ITALSGEN Consortium is a network of around-the-world experts, academics, and practitioners working together to provide real-time information about the human brain’s response to ALS, and to provide a scaffolding for future research.
651 citations
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TL;DR: Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia and Charcot-Marie-Tooth type 2.
444 citations
Cited by
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TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
4,153 citations
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National Institutes of Health1, Cardiff University2, Erasmus University Rotterdam3, VU University Amsterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Georgetown University9, Johns Hopkins University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
3,784 citations
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TL;DR: The wide range of immune-related adverse effects associated with immune checkpoint blockade can complicate this effective therapy and limit its use in patients with cancer.
Abstract: Side Effects of Immune Checkpoint Blockade The wide range of immune-related adverse effects associated with immune checkpoint blockade can complicate this effective therapy and limit its use in patients with cancer. This review surveys the adverse effects and their management.
2,658 citations
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National Institutes of Health1, University College London2, Mayo Clinic3, University of Toronto4, Brigham Young University5, Cardiff University6, Lille University of Science and Technology7, Washington University in St. Louis8, University of Nottingham9, King's College London10, University of Cambridge11
TL;DR: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease.
Abstract: BACKGROUND:
Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.
METHODS:
We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.
RESULTS:
We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.
CONCLUSIONS:
Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).
2,333 citations
01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.
2,187 citations