Correction to: Genome-wide sequencing as a first-tier screening test for short tandem repeat expansions

Microsatellite mining is a common outcome of the in silico approach to genomic studies. The resulting short tandemly repeated DNA could be used as molecular markers for studying polymorphism, genotyping and forensics. The omni short tandem repeat finder and primer designer (OSTRFPD) is among the few versatile, platform-independent open-source tools written in Python that enables researchers to identify and analyse genome-wide short tandem repeats in both nucleic acids and protein sequences. OSTRFPD is designed to run either in a user-friendly fully featured graphical interface or in a command line interface mode for advanced users. OSTRFPD can detect both perfect and imperfect repeats of low complexity with customisable scores. Moreover, the software has built-in architecture to simultaneously filter selection of flanking regions in DNA and generate microsatellite-targeted primers implementing the Primer3 platform. The software has built-in motif-sequence generator engines and an additional option to use the dictionary mode for custom motif searches. The software generates search results including general statistics containing motif categorisation, repeat frequencies, densities, coverage, guanine–cytosine (GC) content, and simple text-based imperfect alignment visualisation. Thus, OSTRFPD presents users with a quick single-step solution package to assist development of microsatellite markers and categorise tandemly repeated amino acids in proteome databases. Practical implementation of OSTRFPD was demonstrated using publicly available whole-genome sequences of selected Plasmodium species. OSTRFPD is freely available and open-sourced for improvement and user-specific adaptation.

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Analysis of short tandem repeat expansions and their methylation state with nanopore sequencing

Nature Biotechnology ◽

10.1038/s41587-019-0293-x ◽

2019 ◽

Vol 37 (12) ◽

pp. 1478-1481 ◽

Cited By ~ 18

Author(s):

Pay Giesselmann ◽

Björn Brändl ◽

Etienne Raimondeau ◽

Rebecca Bowen ◽

Christian Rohrandt ◽

...

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Nanopore Sequencing ◽

Methylation State ◽

Repeat Expansions ◽

Short Tandem

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STRetch: detecting and discovering pathogenic short tandem repeat expansions

Genome Biology ◽

10.1186/s13059-018-1505-2 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 46

Author(s):

Harriet Dashnow ◽

Monkol Lek ◽

Belinda Phipson ◽

Andreas Halman ◽

Simon Sadedin ◽

...

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Repeat Expansions ◽

Short Tandem

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

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01201-x ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Sanjog R. Chintalaphani ◽

Sandy S. Pineda ◽

Ira W. Deveson ◽

Kishore R. Kumar

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Fragile X ◽

Cost Effective ◽

Repeat Expansion ◽

Main Body ◽

Cgg Repeat ◽

Long Read ◽

Repeat Expansions ◽

Short Tandem

Abstract 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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Genome-Wide Sequencing as a First-Tier Screening Test for Short Tandem Repeat Expansions

10.1101/2020.06.06.137356 ◽

2020 ◽

Author(s):

Indhu-Shree Rajan-Babu ◽

Junran Peng ◽

Readman Chiu ◽

Arezoo Mohajeri ◽

Egor Dolzhenko ◽

...

Keyword(s):

Decision Tree ◽

Sensitivity And Specificity ◽

Genome Sequence ◽

Tandem Repeat ◽

Short Tandem Repeat ◽

Sequence Data ◽

Repeat Expansion ◽

Full Mutation ◽

Genome Wide ◽

Short Tandem

ABSTRACTShort tandem repeat (STR) expansions cause several neurological and neuromuscular disorders. Screening for STR expansions in genome-wide (exome and genome) sequencing data can enable diagnosis, optimal clinical management/treatment, and accurate genetic counselling of patients with repeat expansion disorders. We assessed the performance of lobSTR, HipSTR, RepeatSeq, ExpansionHunter, TREDPARSE, GangSTR, STRetch, and exSTRa – bioinformatics tools that have been developed to detect and/or genotype STR expansions – on experimental and simulated genome sequence data with known STR expansions aligned using two different aligners, Isaac and BWA. We then adjusted the parameter settings to optimize the sensitivity and specificity of the STR tools and fed the optimized results into a machine-learning decision tree classifier to determine the best combination of tools to detect full mutation expansions with high diagnostic sensitivity and specificity. The decision tree model supported using ExpansionHunter’s full mutation calls with those of either STRetch or exSTRa for detection of full mutations with precision, recall, and F1-score of 90%, 100%, and 95%, respectively.We used this pipeline to screen the BWA-aligned exome or genome sequence data of 306 families of children with suspected genetic disorders for pathogenic expansions of known disease STR loci. We identified 27 samples, 17 with an apparent full-mutation expansion of the AR, ATXN1, ATXN2, ATXN8, DMPK, FXN, HTT, or TBP locus, nine with an intermediate or premutation allele in the FMR1 locus, and one with a borderline allele in the ATXN2 locus. We report the concordance between our bioinformatics findings and the clinical PCR results in a subset of these samples. Implementation of our bioinformatics workflow can improve the detection of disease STR expansions in exome and genome sequence diagnostics and enhance clinical outcomes for patients with repeat expansion disorders.

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Genome-wide detection of short tandem repeat expansions by long-read sequencing

BMC Bioinformatics ◽

10.1186/s12859-020-03876-w ◽

2020 ◽

Vol 21 (S21) ◽

Author(s):

Qian Liu ◽

Yao Tong ◽

Kai Wang

Keyword(s):

Tandem Repeat ◽

Short Tandem Repeat ◽

Human Diseases ◽

Spinocerebellar Ataxia Type ◽

Human Populations ◽

Normal Ranges ◽

Long Read ◽

Repeat Expansions ◽

Genomic Scale ◽

Short Tandem

Abstract Background Short tandem repeat (STR), or “microsatellite”, is a tract of DNA in which a specific motif (typically < 10 base pairs) is repeated multiple times. STRs are abundant throughout the human genome, and specific repeat expansions may be associated with human diseases. Long-read sequencing coupled with bioinformatics tools enables the estimation of repeat counts for STRs. However, with the exception of a few well-known disease-relevant STRs, normal ranges of repeat counts for most STRs in human populations are not well known, preventing the prioritization of STRs that may be associated with human diseases. Results In this study, we extend a computational tool RepeatHMM to infer normal ranges of 432,604 STRs using 21 long-read sequencing datasets on human genomes, and build a genomic-scale database called RepeatHMM-DB with normal repeat ranges for these STRs. Evaluation on 13 well-known repeats show that the inferred repeat ranges provide good estimation to repeat ranges reported in literature from population-scale studies. This database, together with a repeat expansion estimation tool such as RepeatHMM, enables genomic-scale scanning of repeat regions in newly sequenced genomes to identify disease-relevant repeat expansions. As a case study of using RepeatHMM-DB, we evaluate the CAG repeats of ATXN3 for 20 patients with spinocerebellar ataxia type 3 (SCA3) and 5 unaffected individuals, and correctly classify each individual. Conclusions In summary, RepeatHMM-DB can facilitate prioritization and identification of disease-relevant STRs from whole-genome long-read sequencing data on patients with undiagnosed diseases. RepeatHMM-DB is incorporated into RepeatHMM and is available at https://github.com/WGLab/RepeatHMM.

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Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy

International Journal of Molecular Sciences ◽

10.3390/ijms20133365 ◽

2019 ◽

Vol 20 (13) ◽

pp. 3365 ◽

Cited By ~ 13

Author(s):

Łukasz J. Sznajder ◽

Maurice S. Swanson

Keyword(s):

Myotonic Dystrophy ◽

Tandem Repeat ◽

Short Tandem Repeat ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Foci ◽

Repeat Expansions ◽

Multivalent Interactions ◽

Short Tandem

Short tandem repeat (STR) or microsatellite, expansions underlie more than 50 hereditary neurological, neuromuscular and other diseases, including myotonic dystrophy types 1 (DM1) and 2 (DM2). Current disease models for DM1 and DM2 propose a common pathomechanism, whereby the transcription of mutant DMPK (DM1) and CNBP (DM2) genes results in the synthesis of CUG and CCUG repeat expansion (CUGexp, CCUGexp) RNAs, respectively. These CUGexp and CCUGexp RNAs are toxic since they promote the assembly of ribonucleoprotein (RNP) complexes or RNA foci, leading to sequestration of Muscleblind-like (MBNL) proteins in the nucleus and global dysregulation of the processing, localization and stability of MBNL target RNAs. STR expansion RNAs also form phase-separated gel-like droplets both in vitro and in transiently transfected cells, implicating RNA-RNA multivalent interactions as drivers of RNA foci formation. Importantly, the nucleation and growth of these nuclear foci and transcript misprocessing are reversible processes and thus amenable to therapeutic intervention. In this review, we provide an overview of potential DM1 and DM2 pathomechanisms, followed by a discussion of MBNL functions in RNA processing and how multivalent interactions between expanded STR RNAs and RNA-binding proteins (RBPs) promote RNA foci assembly.

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