Optical genome mapping unveils hidden structural variants in neurodevelopmental disorders
Isabelle Schrauwen1, Yasmin Rajendran2, Anushree Acharya2
1Department of Neurology, Center for Statistical Genetics, Gertrude H. Sergievsky Center, Columbia University Medical Center, Columbia University, 630 W 168Th St, New York, NY, 10032, USA. is2632@cumc.columbia.edu.
Scientific Reports
|May 16, 2024
Summary
Optical genome mapping (OGM) effectively detects structural variants (SVs) missed by short-read sequencing, aiding in diagnosing neurodevelopmental disorders (NDDs). This method identified pathogenic variants in 10.6% of unsolved NDD cases.
Area of Science:
- Genetics
- Genomics
- Molecular Biology
Background:
- Short-read sequencing is standard for genetic research but often misses complex structural variants (SVs) crucial for understanding neurodevelopmental disorders (NDDs).
- Optical genome mapping (OGM) offers a powerful alternative for detecting SVs that are difficult or impossible to identify with current sequencing technologies.
Purpose of the Study:
- To investigate the utility of OGM in identifying causative genetic variants in neurodevelopmental disorder (NDD) cases that were previously unsolved by standard exome sequencing.
- To evaluate OGM's capability in detecting various types of structural variants, including large insertions, inversions, and copy number variations.
Main Methods:
- Optical genome mapping (OGM) was performed on ultra-high molecular weight DNA from 47 families with unsolved neurodevelopmental disorders (NDDs).
- Single-molecule maps were generated and analyzed for structural variants (SVs) and copy number variants (CNVs).
- Identified variants were assessed for pathogenicity, with a focus on those missed by prior exome sequencing.
Main Results:
- OGM identified 7 variants of interest, with 5 (10.6%) classified as likely pathogenic or pathogenic in genes including BCL11A, OPHN1, PHF8, SON, and NFIA.
- A novel inversion disrupting the NAALADL2 gene was detected, a gene previously implicated in NDDs with complex rearrangements.
- Variants missed by exome sequencing primarily included large insertions (>1 kbp), inversions, and small deletions/duplications affecting 1-4 exons.
Conclusions:
- Optical genome mapping (OGM) significantly enhances the molecular diagnosis of neurodevelopmental disorders (NDDs) by detecting complex structural variants (SVs) missed by exome sequencing.
- OGM has the potential to uncover novel NDD genes associated with complex SVs, expanding our understanding of genetic contributions to these disorders.
