TY  - JOUR
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
Y1  - 2025/04/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 810 
EP  - 823 
DO  - 10.1101/gr.279491.124 
VL  - 35 
IS  - 4 
UR  - http://genome.cshlp.org/content/35/4/810.abstract 
N2  - 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. 
ER  -