Repeat Detector: accurate, efficient, and flexible sizing of expanded CAG/CTG repeats from targeted DNA sequencing

Taylor, A. S.; Barros, D.; Gobet, N.; Schuepbach, T.; McAllister, B.; Aeschbach, L.; Randall, E. L.; Trofimenko, E.; Heuchan, E. R.; Barszcz, P.; Ciosi, M.; Morgan, J.; Hafford-Tear, N. J.; Davidson, A. E.; Massey, T. H.; Monckton, D. G.; Jones, L.; REGISTRY Investigators of the European Huntington's disease network,; Xenarios, I.; Dion, V.

doi:10.1101/2022.03.08.483398

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bioRxiv · 10.1101/2022.03.08.483398

Repeat Detector: accurate, efficient, and flexible sizing of expanded CAG/CTG repeats from targeted DNA sequencing

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Abstract

Targeted DNA sequencing approaches will improve how the size of short tandem repeats is measured for diagnostic tests and pre-clinical studies. The expansion of these sequences causes dozens of disorders, with longer tracts generally leading to a more severe disease. Interrupted alleles are sometimes present within repeats and can alter disease manifestation. Determining repeat size mosaicism and identifying interruptions in targeted sequencing datasets remains a major challenge. This is in part because standard alignment tools are ill-suited for repetitive and unstable sequences. To address this, we have developed Repeat Detector (RD), a deterministic profile weighting algorithm for counting repeats in targeted sequencing data. We tested RD using blood-derived DNA samples from Huntingtons disease and Fuchs endothelial corneal dystrophy patients sequenced using either Illumina MiSeq or Pacific Biosciences single-molecule, real-time sequencing platforms. RD was highly accurate in determining repeat sizes of 609 blood-derived samples from Huntingtons disease individuals and did not require prior knowledge of the flanking sequences. Furthermore, RD can be used to identify alleles with interruptions and provide a measure of repeat instability within an individual. RD is therefore highly versatile and may find applications in the diagnosis of expanded repeat disorders and the development of novel therapies.

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Taylor, A. S., Barros, D., Gobet, N., Schuepbach, T., McAllister, B., Aeschbach, L., Randall, E. L., Trofimenko, E., Heuchan, E. R., Barszcz, P., Ciosi, M., Morgan, J., Hafford-Tear, N. J., Davidson, A. E., Massey, T. H., Monckton, D. G., Jones, L., REGISTRY Investigators of the European Huntington's disease network,, Xenarios, I., Dion, V.. 2022-03-09. Repeat Detector: accurate, efficient, and flexible sizing of expanded CAG/CTG repeats from targeted DNA sequencing. https://doi.org/10.1101/2022.03.08.483398

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