RT Journal
A1 van der Sanden, Bart
A1 Neveling, Kornelia
A1 Shukor, Syukri
A1 Gallagher, Michael D.
A1 Lee, Joyce
A1 Burke, Stephanie L.
A1 Pennings, Maartje
A1 van Beek, Ronald
A1 Oorsprong, Michiel
A1 Kater-Baats, Ellen
A1 Kamping, Eveline
A1 Tieleman, Alide A.
A1 Voermans, Nicol C.
A1 Scheffer, Ingrid E.
A1 Gecz, Jozef
A1 Corbett, Mark A.
A1 Vissers, Lisenka E.L.M.
A1 Pang, Andy Wing Chun
A1 Hastie, Alex
A1 Kamsteeg, Erik-Jan
A1 Hoischen, Alexander
T1 Optical genome mapping enables accurate testing of large repeat expansions
JF Genome Research 
JO Genome Research 
YR 2025 
FD April 01 
VO 35 
IS 4 
SP 810 
OP 823 
DO 10.1101/gr.279491.124 
UL http://genome.cshlp.org/content/35/4/810.abstract 
AB 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.