Combining optical genome mapping and RNA-seq for structural variants detection and interpretation in unsolved
Bing Xiao1, Xiaomei Luo1, Yi Liu1
1Department of Pediatric Endocrinology and Genetic Metabolism, Science and Education Building, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Room 801, No.1665, Kong Jiang Road, Shanghai, 200092, China.
Genome Medicine
|September 19, 2024
Summary
Optical genome mapping (OGM) and RNA sequencing (RNA-seq) effectively detect and interpret structural variations (SVs) in neurodevelopmental disorders (NDDs) that are missed by exome sequencing (ES). This combined approach aids in diagnosing complex genetic cases, improving genetic testing for NDDs.
Area of Science:
- Genomics
- Molecular Biology
- Medical Genetics
Background:
- Structural variations (SVs) are significant genetic causes of neurodevelopmental disorders (NDDs).
- Exome sequencing (ES) has limitations in detecting SVs, creating a diagnostic gap.
- Optical genome mapping (OGM) is an emerging technology addressing SV detection challenges.
Purpose of the Study:
- To evaluate the combined utility of OGM and RNA-seq for detecting and interpreting SVs in NDD patients with inconclusive ES results.
- To assess the diagnostic yield of integrating these advanced genomic techniques.
Main Methods:
- OGM was performed on 43 NDD patients with inconclusive ES results.
- Candidate SVs were identified, validated, and reconstructed using methods like long-read sequencing.
- RNA-sequencing (RNA-seq) was used to assess the pathogenicity of identified SVs by analyzing gene expression.
Main Results:
- The combined OGM and RNA-seq approach identified four candidate SVs, confirming pathogenicity in three cases.
- Diagnoses were achieved for two autosomal dominant NDDs (MBD5 deletion, PAFAH1B1 duplication) and one autosomal recessive NDD (PLA2G6 duplication).
- A complex rearrangement involving chromosomes 2 and 6 was detected by OGM, but its pathogenicity remained uncertain due to preserved gene expression.
Conclusions:
- OGM is valuable for identifying SVs, especially in non-coding regions, and characterizing complex rearrangements.
- RNA-seq aids in interpreting the functional impact of SVs at the transcriptional level.
- Combining OGM and RNA-seq offers a powerful and feasible strategy for diagnosing ES-negative NDD cases.
