Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition, 2025, Vollger et al.

Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition
Vollger, Mitchell R.; Korlach, Jonas; Eldred, Kiara C.; Swanson, Elliott; Underwood, Jason G.; Bohaczuk, Stephanie C.; Mao, Yizi; Cheng, Yong-Han H.; Ranchalis, Jane; Blue, Elizabeth E.; Schwarze, Ulrike; Munson, Katherine M.; Saunders, Christopher T.; Wenger, Aaron M.; Allworth, Aimee; Chanprasert, Sirisak; Duerden, Brittney L.; Glass, Ian; Horike-Pyne, Martha; Kim, Michelle; Leppig, Kathleen A.; McLaughlin, Ian J.; Ogawa, Jessica; Rosenthal, Elisabeth A.; Sheppeard, Sam; Sherman, Stephanie M.; Strohbehn, Samuel; Yuen, Amy L.; Stacey, Andrew W.; Reh, Thomas A.; Byers, Peter H.; Bamshad, Michael J.; Hisama, Fuki M.; Jarvik, Gail P.; Sancak, Yasemin; Dipple, Katrina M.; Stergachis, Andrew B.

Resolving the molecular basis of a Mendelian condition remains challenging owing to the diverse mechanisms by which genetic variants cause disease.

To address this, we developed a synchronized long-read genome, methylome, epigenome and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion–deletion and structural variant calling and diploid de novo genome assembly. This permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility and full-length transcript information in a single long-read sequencing run.

Application of this approach to an Undiagnosed Diseases Network participant with a chromosome X;13-balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA, PDK3, MAB21L1 and RB1) previously associated with single-gene Mendelian conditions. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four ‘omes’ to resolve. These included fusion transcript formation, enhancer adoption, transcriptional readthrough silencing and inappropriate X-chromosome inactivation of autosomal genes.

Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.

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