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<p>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 (<i>NBEA</i>, <i>PDK3</i>, <i>MAB21L1</i> and <i>RB1</i>) 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年1月29日

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

摘要

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.