Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS

Nakamura, Hajime; Doi, Hiroshi; Mitsuhashi, Satomi; Miyatake, Satoko; Katoh, Kazutaka; Frith, Martin C.; Asano, Tetsuya; Kudo, Yoshihisa; Ikeda, Takuya; Kubota, Shohei; Kunii, Misako; Kitazawa, Yu; Tada, Mikiko; Okamoto, M.; Joki, Hideto; Takeuchi, Hideyuki; Matsumoto, Naomichi; Tanaka, Fumiaki

doi:10.1038/s10038-020-0733-y

Cited by 44 publications

(47 citation statements)

References 18 publications

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“…Long-read sequencing can also be successfully employed to detect pathological repeat expansions as shown by Nakamura et al [16]. Briefly, they obtained long reads from the patient and normal control DNA using PromethION sequencer (Oxford Nanopore Technologies, Oxford Science Park, UK).…”

Section: Investigation Methods For Pentanucleotide Expansionsmentioning

confidence: 99%

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CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

Dominik¹,

Deforie²,

Cortese

et al. 2020

J Neurol

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The ataxias are a group of disorders that manifest with balance, movement, speech and visual problems. They can arise due to dysfunction of the cerebellum, the vestibular system and/or the sensory neurons. Genetic defects are a common cause of chronic ataxia, particularly common are repeat expansions in this group of conditions. Co-occurrence of cerebellar ataxia with neuropathy and vestibular areflexia syndrome has been termed CANVAS. Although CANVAS is a rare syndrome, on discovery of biallelic expansions in the second intron of replication factor C subunit 1 (RFC1) gene, we and others have found the phenotype is broad and RFC1 expansions are a common cause of late-onset progressive ataxia. We aim to provide a review and update on recent developments in CANVAS and populations, where the disorder has been reported. We have also optimised a protocol for RFC1 expansion screening which is described herein and expanded phenotype after analysing late-onset ataxia patients from around the world.

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Section: Investigation Methods For Pentanucleotide Expansionsmentioning

confidence: 99%

“…A few CANVAS cases were identified in Japan [14][15][16], of which one was genetically confirmed by long read sequencing and it has the same haplotype around RFC1 as most European cases [16].…”

Section: Repeat Expansions In Rfc1mentioning

confidence: 96%

CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

Dominik¹,

Deforie²,

Cortese

et al. 2020

J Neurol

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“…In the study by Sone et al mentioned above, they also used Cas9-mediated enrichment to achieve high sequencing depth (100–1795×) following their initial low-coverage whole-genome sequencing [ 146 ]. Furthermore, this method aided in identifying a ‘AAGGG’ repeat in a Japanese family in the RFC1 gene as well as benign ‘TAAAA’ and ‘TAGAA’ expansions in BEAN1 [ 114 ]. Cas9-mediated target enrichment is amenable to multiplexing, making it feasible to target multiple disease alleles in parallel, for more efficient and cost-effective diagnosis.…”

Section: Outlook: Efficient and Accurate Diagnosis Of Repeat Expansion Disorders With Long-read Sequencingmentioning

confidence: 99%

An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

Chintalaphani

Pineda

Deveson

et al. 2021

acta neuropathol commun

106

126

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Background Short tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have an established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington’s disease, the hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia. Main body STR expansions are difficult to detect and may explain unsolved diseases, as highlighted by recent findings including: the discovery of a biallelic intronic ‘AAGGG’ repeat in RFC1 as the cause of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS); and the finding of ‘CGG’ repeat expansions in NOTCH2NLC as the cause of neuronal intranuclear inclusion disease and a range of clinical phenotypes. However, established laboratory techniques for diagnosis of repeat expansions (repeat-primed PCR and Southern blot) are cumbersome, low-throughput and poorly suited to parallel analysis of multiple gene regions. While next generation sequencing (NGS) has been increasingly used, established short-read NGS platforms (e.g., Illumina) are unable to genotype large and/or complex repeat expansions. Long-read sequencing platforms recently developed by Oxford Nanopore Technology and Pacific Biosciences promise to overcome these limitations to deliver enhanced diagnosis of repeat expansion disorders in a rapid and cost-effective fashion. Conclusion We anticipate that long-read sequencing will rapidly transform the detection of short tandem repeat expansion disorders for both clinical diagnosis and gene discovery.

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“…More than 40 diseases have been found to be caused by STR expansions [ 8 ]. Repeat expansions may also be the mechanism underlying other rare diseases that are currently unexplained [ 26 – 31 ]. Efficiently searching for expansions anywhere in the genome would greatly facilitate the identification of novel disease-associated STR loci, but performing a genome-wide search for such expansions with existing long-read genotyping software necessitates interrogating hundreds of thousands of annotated loci (e.g., the UCSC simple repeats track), a time- and resource-intensive process.…”

Section: Introductionmentioning

confidence: 99%

Straglr: discovering and genotyping tandem repeat expansions using whole genome long-read sequences

et al. 2021

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Tandem repeat (TR) expansion is the underlying cause of over 40 neurological disorders. Long-read sequencing offers an exciting avenue over conventional technologies for detecting TR expansions. Here, we present Straglr, a robust software tool for both targeted genotyping and novel expansion detection from long-read alignments. We benchmark Straglr using various simulations, targeted genotyping data of cell lines carrying expansions of known diseases, and whole genome sequencing data with chromosome-scale assembly. Our results suggest that Straglr may be useful for investigating disease-associated TR expansions using long-read sequencing.

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Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS

Cited by 44 publications

References 18 publications

CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

Straglr: discovering and genotyping tandem repeat expansions using whole genome long-read sequences

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