Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders
Mathilde Geysens1,2, Benjamin Huremagic1, Erika Souche1
1Laboratory of Cytogenetics and Genome Research, Centre for Human Genetics, KU Leuven, Leuven, 3000, Belgium.
Genome Medicine
|January 9, 2025
Summary
Long-read nanopore sequencing can detect disease-specific DNA methylation patterns called episignatures in developmental disorders. This method aids in diagnosing genetic conditions by simultaneously analyzing genomic and epigenomic data.
Area of Science:
- Genomics
- Epigenetics
- Bioinformatics
Background:
- Developmental disorders (DD) can exhibit unique genome-wide methylation changes known as episignatures.
- Episignatures are crucial for understanding disease mechanisms, assessing variant pathogenicity, and confirming diagnoses.
- Current methods for episignature detection are indirect; this study explores a direct approach using long-read sequencing.
Purpose of the Study:
- To investigate if long-read whole genome sequencing can detect episignatures in developmental disorders.
- To evaluate the capability of nanopore sequencing to identify single nucleotide variants, structural variants, and episignatures simultaneously.
Main Methods:
- Performed genome-wide nanopore sequencing on 40 controls and 20 patients with suspected episignature-associated DD.
- Called genomic variants and methylomes, then used clustering and dimensional reduction to compare with microarray-based episignatures.
- Developed a support vector machine (SVM) classifier for DD episignature detection.
Main Results:
- Nanopore sequencing methylome patterns aligned with microarray-based episignatures.
- The SVM classifier successfully identified episignatures in 17/19 patients with pathogenic variants, distinguishing them from controls.
- Identified pathogenic single nucleotide and structural variants, and demonstrated the utility of haplotype-aware skewed X-inactivation analysis.
Conclusions:
- Nanopore sequencing is a viable method for detecting episignatures.
- Concurrent genomic and epigenomic analysis via nanopore sequencing integrates variant detection, X-inactivation, and imprinting analysis into a single diagnostic assay.
