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Researchers validated long-read sequencing technologies for analyzing repeat expansions in myotonic dystrophy type 2 (DM2) by comparing Oxford Nanopore and PacBio HiFi platforms across 8 patient samples. The two platforms showed high agreement in measuring repeat sizes and detecting genetic variation, and revealed a previously unreported (CCCG)n motif at the end of expanded CNBP gene sequences. The study also established an improved computational workflow for analyzing these complex repeat sequences.
Why it matters
This cross-platform validation provides a reliable framework for using long-read sequencing to diagnose and study DM2 and similar repeat expansion disorders. The discovery of novel repeat motifs enhances understanding of disease mechanisms and could improve genetic testing accuracy for these conditions.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
The broader application of long-read sequencing (LRS) for repeat expansion characterization in myotonic dystrophy type 2 (DM2) and other repeat expansion disorders (REDs) remains limited by the lack of systematic validation and benchmarking of sequencing results and bioinformatic workflows. Here, we performed an orthogonal cross-platform validation of previously generated Oxford Nanopore Technologies (ONT) data by sequencing the same DNA samples with Pacific Biosciences (PacBio) HiFi following amplification-free targeted enrichment in a cohort of 8 DM2 patients. Despite substantial differences in sequencing chemistry and coverage, the two platforms showed high concordance in repeat size estimation, somatic mosaicism, and repeat architecture. This validation confirmed the presence of the (TCTG)n motif and enabled the identification of a previously unreported (CCCG)n motif at the 3′ end of expanded alleles, further highlighting the structural complexity of the CNBP expansion. Through this analysis, we also established a bioinformatic workflow that improved ONT-based repeat characterization, addressing limitations in motif resolution and enabling more accurate analysis of CNBP expansions. Overall, this study provides a validated framework for LRS-based CNBP repeat analysis, supporting the integration of these technologies into routine molecular investigation for DM2 and other REDs.
Source: Long-read cross-platform validation reveals novel repeat features in myotonic dystrophy type 2