Optical genome mapping enables accurate testing of large repeat expansions
- Bart van der Sanden1,
- Kornelia Neveling1,
- Syukri Shukor2,
- Michael D. Gallagher2,
- Joyce Lee2,
- Stephanie L. Burke2,
- Maartje Pennings1,
- Ronald van Beek1,
- Michiel Oorsprong1,
- Ellen Kater-Baats1,
- Eveline Kamping1,
- Alide A. Tieleman3,
- Nicol C. Voermans3,
- Ingrid E. Scheffer4,5,
- Jozef Gecz6,7,8,
- Mark A. Corbett8,
- Lisenka E.L.M. Vissers1,
- Andy Wing Chun Pang2,
- Alex Hastie2,
- Erik-Jan Kamsteeg1,10 and
- Alexander Hoischen1,9,10
- 1Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands;
- 2Bionano Genomics Clinical and Scientific Affairs, San Diego, California 92101, USA;
- 3Department of Neurology, Radboud University Medical Center, 6525GA Nijmegen, the Netherlands;
- 4Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, VIC 3084, Australia;
- 5Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Florey and Murdoch Children's Research Institutes, VIC 3052, Melbourne, Australia;
- 6South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia;
- 7Genetics and Molecular Pathology, SA Pathology, Adelaide, SA 5000, Australia;
- 8Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia;
- 9Department of Internal Medicine, Radboud Expertise Center for Immunodeficiency and Autoinflammation and Radboud Center for Infectious Disease (RCI), Radboud University Medical Center, 6525GA Nijmegen, the Netherlands
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↵10 These authors jointly supervised the work.
Abstract
Short tandem repeats (STRs) are common variations in human genomes that frequently expand or contract, causing genetic disorders, mainly when expanded. Traditional diagnostic methods for identifying these expansions, such as repeat-primed PCR and Southern blotting, are often labor-intensive, locus-specific, and are unable to precisely determine long repeat expansions. Sequencing-based methods, although capable of genome-wide detection, are limited by inaccuracy (short-read technologies) and high associated costs (long-read technologies). This study evaluated optical genome mapping (OGM) as an efficient, accurate approach for measuring STR lengths and assessing somatic stability in 85 samples with known pathogenic repeat expansions in DMPK, CNBP, and RFC1, causing myotonic dystrophy types 1 and 2 and cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), respectively. Three workflows—manual de novo assembly, local guided assembly (local-GA), and a molecule distance script—were applied, of which the latter two were developed as part of this study to assess the repeat sizes and somatic repeat stability. OGM successfully identified 84/85 (98.8%) of the pathogenic expansions, distinguishing between wild-type and expanded alleles or between two expanded alleles in recessive cases, with greater accuracy than standard of care (SOC) for long repeats and no apparent upper size limit. Notably, OGM detected somatic instability in a subset of DMPK, CNBP, and RFC1 samples. These findings suggest OGM could advance diagnostic accuracy for large repeat expansions, providing a more comprehensive genome-wide assay for repeat expansion disorders by measuring exact repeat lengths and somatic instability across multiple loci simultaneously.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.279491.124.
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Freely available online through the Genome Research Open Access option.
- Received April 19, 2024.
- Accepted February 24, 2025.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
