ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data

Dolzhenko, Egor; Bennett, Mark F; Richmond, Phillip A.; Trost, Brett; Chen, Sai; Vugt, Joke J.F.A. van; Nguyen, Charlotte; Narzisi, Giuseppe; Gainullin, Vladimir G.; Gross, Andrew M.; Lajoie, Bryan R.; Taft, Ryan J.; Wasserman, Wyeth W.; Scherer, Stephen W.; Veldink, Jan H.; Bentley, David; Yuen, Ryan K. C.; Bahlo, Melanie; Eberle, Michael A.

doi:10.1186/s13059-020-02017-z

Cited by 122 publications

(117 citation statements)

References 52 publications

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“…While our work was under review, a study conducted by Trost et al 41 was published that investigated STRs of 2–20 bp in a genome-wide setting and in relation to autism spectrum disorder 41 . In our study, we detected a much higher number of CGG STR loci than Trost and colleagues, as the emphasis of their work was on expanded STR loci utilizing ExpansionHunter Denovo 42 . This algorithm only detects repeat expansions that exceed the length of the sequencing reads, typically 150 bp, corresponding to 50 CGG repeat expansions.…”

Section: Discussionmentioning

confidence: 49%

Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

Annear

Vandeweyer

Elinck

et al. 2021

Sci Rep

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Expanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.

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Section: Discussionmentioning

confidence: 49%

Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

Annear

Vandeweyer

Elinck

et al. 2021

Sci Rep

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“…To screen for extremely long STR expansions (similar to the C9orf72 repeat expansion) at loci that not included in the predefined STR catalogues, we applied ExpansionHunter-Denovo 74 . This method aims to only find STR expansions that exceed the sequencing read-length (> 150 bp) by identifying reads (mapped, mismapped and unmapped) that contain STR motifs, using their mate pairs for de novo mapping to the reference genome.…”

Section: Methodsmentioning

confidence: 99%

“…For all individuals that were sequenced on the HiSeqX dataset (5,392 cases, 1,795 controls) we screened all loci harboring SNPs associated with ALS meeting genome-wide significance for expansions of known and new short tandem repeats (STRs) using ExpansionHunter 73 and ExpansionHunter Denovo 74 .…”

Section: Short Tandem Repeat Screenmentioning

confidence: 99%

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Rheenen

Spek

Bakker

et al. 2021

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

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“…GeneBreaker is hosted on a virtual web server at the Centre for Molecular Medicine and Therapeutics, with 12 GB of RAM and 4 CPUs running CentOS 7. The variant data within the underlying repository comes from open‐source variant catalogs including ClinVar (Landrum et al, 2018), ClinGen (Rehm et al, 2015), and a manually curated set of pathogenic short tandem repeat expansions (Table S1) (Dolzhenko et al, 2020). Gene models come from the RefSeq annotation database provided by the UCSC Genome Browser (NCBI Homo sapiens Annotation Release 109 (March 29, 2018); Haeussler et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

GeneBreaker: Variant simulation to improve the diagnosis of Mendelian rare genetic diseases

et al. 2021

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Mendelian rare genetic diseases affect 5%–10% of the population, and with over 5300 genes responsible for ∼7000 different diseases, they are challenging to diagnose. The use of whole‐genome sequencing (WGS) has bolstered the diagnosis rate significantly. The effective use of WGS relies on the ability to identify the disrupted gene responsible for disease phenotypes. This process involves genomic variant calling and prioritization, and is the beneficiary of improvements to sequencing technology, variant calling approaches, and increased capacity to prioritize genomic variants with potential pathogenicity. As analysis pipelines continue to improve, careful testing of their efficacy is paramount. However, real‐life cases typically emerge anecdotally, and utilization of clinically sensitive and identifiable data for testing pipeline improvements is regulated and limiting. We identified the need for a gene‐based variant simulation framework that can create mock rare disease scenarios, utilizing known pathogenic variants or through the creation of novel gene‐disrupting variants. To fill this need, we present GeneBreaker, a tool that creates synthetic rare disease cases with utility for benchmarking variant calling approaches, testing the efficacy of variant prioritization, and as an educational mechanism for training diagnostic practitioners in the expanding field of genomic medicine. GeneBreaker is freely available at http://GeneBreaker.cmmt.ubc.ca.

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ExpansionHunter Denovo: a computational method for locating known and novel repeat expansions in short-read sequencing data

Cited by 122 publications

References 52 publications

Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

GeneBreaker: Variant simulation to improve the diagnosis of Mendelian rare genetic diseases

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