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Title: REViewer: haplotype-resolved visualization of read alignments in and around tandem repeats.
Austin Authors: Dolzhenko, Egor;Weisburd, Ben;Ibañez, Kristina;Rajan-Babu, Indhu-Shree;Anyansi, Christine;Bennett, Mark F ;Billingsley, Kimberley;Carroll, Ashley;Clamons, Samuel;Danzi, Matt C;Deshpande, Viraj;Ding, Jinhui;Fazal, Sarah;Halman, Andreas;Jadhav, Bharati;Qiu, Yunjiang;Richmond, Phillip A;Saunders, Christopher T;Scheffler, Konrad;van Vugt, Joke J F A;Zwamborn, Ramona R A J;Chong, Samuel S;Friedman, Jan M;Tucci, Arianna;Rehm, Heidi L;Eberle, Michael A
Affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia..
Department of Medical Genetics, University of British Columbia and Children's & Women's Hospital, Vancouver, BC, V6H3N1, Canada..
William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK..
Illumina Inc., San Diego, CA, 92122, USA..
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia..
Epilepsy Research Centre
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia..
Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia..
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA..
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA..
Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA..
Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore..
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA..
Department of Laboratory Medicine, National University Hospital, Singapore, 119074, Singapore..
Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, 20892, USA..
Center for Genomic Medicine, Massachusetts General Hospital, Boston, USA..
Department of Genetics and Genomic Sciences and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA..
BC Children's Hospital Research Institute, Vancouver, BC, V5Z 4H4, Canada..
Department of Neurology, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands..
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore..
Department of Medical and Molecular Genetics, King's College London, Strand, London, WC2R 2LS, UK..
Issue Date: 11-Aug-2022
Date: 2022
Publication information: Genome Medicine 2022; 14(1): 84
Abstract: Expansions of short tandem repeats are the cause of many neurogenetic disorders including familial amyotrophic lateral sclerosis, Huntington disease, and many others. Multiple methods have been recently developed that can identify repeat expansions in whole genome or exome sequencing data. Despite the widely recognized need for visual assessment of variant calls in clinical settings, current computational tools lack the ability to produce such visualizations for repeat expansions. Expanded repeats are difficult to visualize because they correspond to large insertions relative to the reference genome and involve many misaligning and ambiguously aligning reads. We implemented REViewer, a computational method for visualization of sequencing data in genomic regions containing long repeat expansions and FlipBook, a companion image viewer designed for manual curation of large collections of REViewer images. To generate a read pileup, REViewer reconstructs local haplotype sequences and distributes reads to these haplotypes in a way that is most consistent with the fragment lengths and evenness of read coverage. To create appropriate training materials for onboarding new users, we performed a concordance study involving 12 scientists involved in short tandem repeat research. We used the results of this study to create a user guide that describes the basic principles of using REViewer as well as a guide to the typical features of read pileups that correspond to low confidence repeat genotype calls. Additionally, we demonstrated that REViewer can be used to annotate clinically relevant repeat interruptions by comparing visual assessment results of 44 FMR1 repeat alleles with the results of triplet repeat primed PCR. For 38 of these alleles, the results of visual assessment were consistent with triplet repeat primed PCR. Read pileup plots generated by REViewer offer an intuitive way to visualize sequencing data in regions containing long repeat expansions. Laboratories can use REViewer and FlipBook to assess the quality of repeat genotype calls as well as to visually detect interruptions or other imperfections in the repeat sequence and the surrounding flanking regions. REViewer and FlipBook are available under open-source licenses at and respectively.
DOI: 10.1186/s13073-022-01085-z
Journal: Genome Medicine
PubMed URL: 35948990
PubMed URL:
Type: Journal Article
Subjects: Repeat expansions
Short tandem repeats
Short-read sequencing data
Appears in Collections:Journal articles

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