Optical genome mapping enables accurate testing of large repeat expansions

Area of Science:

• Genomics
• Genetic Diagnostics
• Molecular Biology

Background:

• Short tandem repeats (STRs) are genomic variations that can cause genetic disorders upon expansion.
• Current diagnostic methods for STR expansions are often labor-intensive, locus-specific, and lack precision for long repeats.
• Sequencing methods have limitations in accuracy (short-read) or cost (long-read).

Purpose of the Study:

• To evaluate Optical Genome Mapping (OGM) as an efficient and accurate method for measuring STR lengths.
• To assess OGM's capability in detecting pathogenic repeat expansions and somatic instability.
• To compare OGM's performance against standard diagnostic care for repeat expansion disorders.

Main Methods:

• Optical Genome Mapping (OGM) was applied to 85 samples with known pathogenic repeat expansions in DMPK, CNBP, and RFC1.
• Three OGM workflows were utilized: manual de novo assembly, local guided assembly (local-GA), and a molecule distance script.
• The study focused on assessing STR sizes and somatic repeat stability.

Main Results:

• OGM successfully identified 98.8% of pathogenic repeat expansions across the targeted genes.
• The technique accurately distinguished between wild-type and expanded alleles, even in recessive cases.
• OGM demonstrated superior accuracy for long repeats compared to standard of care, with no identified upper size limit.
• Somatic instability was detected in a subset of samples analyzed by OGM.

Conclusions:

• OGM offers a highly accurate and efficient approach for diagnosing large repeat expansions in genetic disorders.
• The technology provides precise measurement of repeat lengths and assessment of somatic instability.
• OGM has the potential to enhance diagnostic accuracy and offer a comprehensive genome-wide assay for repeat expansion disorders.