Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders

Mathilde Geysens; Benjamin Huremagic; Erika Souche; Jeroen Breckpot; Koenraad Devriendt; Hilde Peeters; Buggenhout Griet Van; Esch Hilde Van; Den Bogaert Kris Van; Vermeesch Joris Robert

doi:10.1530/ey.22.14.8

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 14.8 | DOI: 10.1530/ey.22.14.8

ESPEYB25 14. The Year in Science and Medicine Genomics – Long-Read Sequencing (7 abstracts)

14.8. Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders

Mathilde Geysens , Benjamin Huremagic , Erika Souche , Jeroen Breckpot , Koenraad Devriendt , Hilde Peeters , Griet Van Buggenhout , Hilde Van Esch , Kris Van Den Bogaert & Joris Robert Vermeesch

Genome Med. 2025;17(1):1. doi: 10.1186/s13073-024-01419-z

Brief Summary: These authors performed long-read whole genome sequencing (lrWGS; Oxford Nanopore technology) on 20 patients, representing 13 developmental disorders (DD) with known episignatures, and 40 controls to show proof-of-concept that lrWGS can simultaneously detect genomic variants (single nucleotide and structural variants) and disease-specific methylation signatures (“episignatures”) in developmental disorders (DD).

Using lrWGS and hierarchical clustering, dimensionality reduction, and a custom support vector machine classifier, they correctly identified episignatures in 17 of 19 patients carrying (likely) pathogenic variants, with no false positives in the controls. The remaining two patients were classified as controls both by nanopore and microarray assays, demonstrating high concordance with standard methods. In addition, lrWGS successfully detected all underlying SNVs and structural variants and provided haplotype-aware analyses of X-chromosome inactivation and imprinting.

These findings show that lrWGS is an all-in-one diagnostic platform that is able to detect genetic variants, structural variants, and profile methylation; all in a single assay. As opposed to traditional diagnostics, which typically require multiple separate tests (e.g. exome sequencing, methylation assays and X-chromosome inactivation studies), lrWGS shows promise as a single comprehensive genetic assay that could streamline diagnostics, reduce costs and turnaround time, as well as patient burden. However, further development of long-read-specific episignature databases and classifiers is needed for broader clinical adoption.