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

[SNT Gatchaman]

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.

Link | PDF (Nature Genetics)

 

[SNT Gatchaman]

The diagnosis of Mendelian conditions is challenged by the ability to detect pathogenic genetic variation accurately and to determine whether an identified genetic variant has a functional consequence. Recent advances in accurate long-read sequencing have markedly improved our ability to detect genetic variants, yet our ability to determine whether an identified genetic variant has a functional consequence remains quite limited. This challenge is particularly acute when evaluating noncoding genetic variants owing to the >4 million noncoding variants harbored in each genome and the diverse mechanisms by which noncoding variants can cause disease. Multi-omic approaches have shown promise in resolving this challenge by integrating genomic information with functional information from the same sample

Accurate long-read sequencing has the potential to resolve these limitations through haplotype-phased epigenetic and transcriptomic information. Specifically, accurate long-read sequencing permits the simultaneous detection of CpG methylation information on each sequenced read, which provides a direct evaluation of the impact of genetic variants on CpG methylation patterns.

It is anticipated that this approach will enable clinicians and researchers to better understand how diverse classes of genetic variation mechanistically drive human diseases, as well as potential molecular targets for modulating these diseases.