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Clinical Feasibility of Long-Read WGS for DNA Methylation Signature Analysis
Mathis Hildonen1, Luca Mariani2, Jonas Dalsberg1
1Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.
Clinical Genetics
|November 12, 2025
Summary
Long-read sequencing (LRS) accurately captures DNA methylation (DNAm) profiles, aligning with array-based methods for diagnosing rare genetic disorders. LRS offers a promising alternative for clinical diagnostics, enabling simultaneous methylation and sequence analysis.
Area of Science:
- Genomics
- Epigenetics
- Biomarker Discovery
Background:
- DNA methylation (DNAm) signatures are crucial biomarkers for rare genetic disorders.
- Array-based technologies have been standard for DNAm signature analysis.
- Clinical diagnostics are increasingly adopting long-read sequencing (LRS) over short-read sequencing (SRS).
Purpose of the Study:
- To compare DNA methylation profiles generated by LRS platforms (PacBio, ONT) with traditional DNA methylation arrays.
- To evaluate the feasibility of LRS for DNAm-based diagnostics in rare genetic disorders.
- To assess the concordance between LRS and array-based DNAm signatures.
Main Methods:
- Analysis of DNA methylation profiles from two individuals with KMT2D variants using DNAm arrays.
- Generation of DNAm profiles using PacBio and Oxford Nanopore Technologies (ONT) LRS platforms.
- Utilized ONT multiplexed sequencing with adaptive sampling.
- Employed a support vector machine (SVM) classifier trained on array data and the EpigenCentral platform for predictions.
Main Results:
- LRS-generated DNA methylation profiles showed strong alignment with array-based signatures.
- A classifier trained on array data correctly predicted outcomes for all LRS samples.
- LRS platforms demonstrated potential for accurate DNAm-based diagnostics.
Conclusions:
- Long-read sequencing platforms are feasible for generating DNA methylation profiles comparable to array-based methods.
- LRS holds significant promise for clinical and research applications in DNAm-based diagnostics.
- LRS offers the advantage of simultaneous DNA methylation and sequence analysis.
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