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

Area of Science:

• Genomics
• Epigenetics
• Transcriptomics
• Systems Biology

Background:

• Mendelian conditions pose diagnostic challenges due to diverse genetic variant mechanisms.
• Understanding these mechanisms requires integrated multi-omic data.
• Current methods often struggle to resolve complex genetic disruptions.

Purpose of the Study:

• To develop and apply a synchronized long-read multi-omic sequencing approach.
• To enable simultaneous analysis of genome, methylome, epigenome, and transcriptome.
• To mechanistically resolve complex phenotypes caused by genetic variants.

Main Methods:

• Developed a synchronized long-read sequencing strategy.
• Integrated genome, methylome, epigenome, and transcriptome data.
• Applied the method to an Undiagnosed Diseases Network participant with a translocation.

Main Results:

• Accurate calling of single-nucleotide, insertion-deletion, and structural variants.
• Diploid de novo genome assembly and haplotype-resolved multi-omic data.
• Identified disruption of four genes (NBEA, PDK3, MAB21L1, RB1) by a chromosome X;13 translocation.
• Uncovered distinct disruption mechanisms: fusion transcripts, enhancer adoption, readthrough silencing, and inappropriate X-inactivation.

Conclusions:

• Synchronized long-read multi-omic profiling is powerful for resolving complex genetic diseases.
• This approach integrates diverse data to elucidate novel disease mechanisms.
• Facilitates mechanistic understanding of Mendelian conditions with complex genetic underpinnings.