Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition

Vollger Mitchell R.; Jonas Korlach; Eldred Kiara C.; Elliott Swanson; Underwood Jason G.; Bohaczuk Stephanie C.; et al

doi:10.1530/ey.22.14.5

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 14.5 | DOI: 10.1530/ey.22.14.5

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

14.5. Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition

Mitchell R. Vollger , Jonas Korlach , Kiara C. Eldred , Elliott Swanson , Jason G. Underwood , Stephanie C. Bohaczuk & et al

Nat Genet. 2025;57(2):469-79. doi: 10.1038/s41588-024-02067-0

Brief Summary: This genetic case study used a synchronized long-read sequencing approach that simultaneously profiles the genome, CpG methylome, chromatin epigenome, and transcriptome from a single sample. It revealed the complex genetic disorder of a patient with an unsolved Mendelian condition. This method identified a balanced X;13 translocation that disrupted four genes (NBEA, PDK3, MAB21L1, and RB1), each through a distinct molecular mechanism. The integrated multi-omic strategy enabled the resolution of complex gene regulatory disruptions that would have been missed by conventional sequencing methods.

This study demonstrates the power of synchronized long-read multi-omic profiling to uncover the mechanistic basis of complex genetic disorders, especially those involving structural variants and non-coding regions. This approach is expected to empower clinicians and researchers with deeper insights into how various forms of genetic variation contribute to disease mechanisms, while also uncovering novel molecular targets for therapeutic intervention.

Further studies are needed to assess the generalizability of this approach across diverse genetic disorders and tissues. Furthermore, integration with clinical workflows and cost-effectiveness analyses is essential for broader adoption.