On Day 3 of the Bionano Symposium 2023, experts from around the world shared exciting work in applying optical genome mapping (OGM) to uncover genetic variation that contributes to constitutional genetic diseases.
Cytogenetic techniques, such as karyotyping, fluorescent in situ hybridization (FISH), and chromosomal microarray analysis (CMA), have traditionally been used to identify and report structural variants (SVs) in constitutional genetic disease research. These technologies have limitations, and many SVs remain unseen. Over recent years, the use of next-generation sequencing technologies, to supplement cytogenetic assays, has emerged, on the quest to reveal other causative variants. Still, many samples remain unsolved.
Today’s sessions explored how analysis of SVs using OGM is increasing the likelihood of finding actionable pathogenic variants—sometimes in investigating unresolved samples—even after exome sequencing, supporting OGM as a strong alternative to these traditional workflows.
Register now to join us live this week and view recorded sessions after 1/26/23 on the Bionano Symposium 2023 virtual event platform.
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On the third day of presentations, experts shared data and experiences validating and working with OGM technology from Bionano. OGM validation and study data were compared to standard cytogenomic methods (such as karyotyping, microarray, FISH, and Southern Blot) and consistently showed very high to perfect concordance. In most of the studies presented, OGM clearly showed a further increase in the detection of reportable findings.
In one example, Dr. Levy from Columbia University Medical Center presented data on a multicenter study evaluating the use of OGM for prenatal genetic analysis. He highlighted the study’s design and OGM’s capacity as a high-performance, one-stop platform, potentially eliminating the need for multiple sequential testing.
Some of today’s presenters promoted OGM as a single “next-generation cytogenomics platform” and framed its demonstrated benefits and low risk profile as a first-tier tool for constitutional disease analysis.
Dr. Stevenson from Greenwood Genetic Center, for example, discussed a large multisite study focusing on postnatal constitutional disorders such as intellectual disability, autism, and birth defects in males and females. He presented substantial data to support the use of OGM as a single cytogenomic platform that can detect all classes of SVs and argued for its use as a first-tier assay.
The use of OGM in combination with next-generation sequencing (NGS) technologies was also discussed as a way to uncover hidden insights, specifically when analyzing de novo SVs in trio analysis—and also in providing insights helpful in the investigation of unresolved samples.
Dr. Alexander Hoischen from Radboud University Medical Center presented data on using OGM’s unbiased genome-wide approach for rare disease investigation in trio analysis . He also provided use cases to support his argument that OGM is a next-generation cytogenomics platform and could be used as a first-tier assay for complex workups, including those involving hematological malignancies and constitutional genetic disorders, as well as other interesting use cases.
In another presentation, Dr. Detlef Trost, from the CERBA Lab in France, presented additional data on the potential of OGM to improve workups for difficult samples. He examined whether OGM can help researchers uncover informative insights and identify new candidate genes to explore.
Dr. Schrauwen, from Columbia University, New York, presented data on using OGM to uncover insights required to resolve unsolved neurodevelopmental samples missed by traditional methods such as short-read sequencing and microarray. She emphasized the ability of OGM to detect complex variations.
Presenters also shared their experiences of easily implementing OGM into their lab, pointing out its low operationalization risk, low training barriers, and quick positive impact on their lab.
Dr. Garoz, from Hospital Nino Jesus, Spain, presented data on her team’s recent validation activities and experiences in their lab. She summarized the benefits and limitations of the technology and broke down the performance by cytogenetic assay, concluding with an assessment of the positive impact of OGM on her lab operations.
Presentation No. 1
Roger E. Stevenson | Senior Clinical Geneticist | Equanimitas
Dr. Stevenson, from Equiminitas, presented a high-level review of neural tube defects (NTDs), a collective term for common birth defects of the brain, spine, or spinal cord that occur early in pregnancy. He covered the embryology, clinical presentations, prevalence as well as prevention measures, finishing off with a review of genetic and environmental risk factors.
Dr. Stevenson then shared his experience using OGM with a cohort of 85 NTD study participants and demonstrated OGM’s high-resolution and powerful circo plot interpretation data to accurately detect a comprehensive range of pathogenic variants.
Furthermore, he highlighted OGM’s enhanced ability to survey structural variants at specific gene locations, providing useful information for research and discovery of NTDs.
“Of equivalent importance, is the fact that structural variants were found in the human equivalent of mouse neural detect genes and other neural defect pathway genes”.
Presentation No. 2
Brynn Levy, M.Sc.(Med)., Ph.D., FACMG | Professor of Pathology & Cell Biology | Columbia University Medical Center
Dr. Levy presented data from a multicenter study that evaluated and validated OGM as a transformative solution for testing constitutional genetic diseases. He compared OGM to standard cytogenomic methods such as karyotyping, microarray, FISH, and Southern Blot, showing that OGM consistently had very high to perfect concordance.
He also presented data from a prenatal multisite study that demonstrated OGM’s ability to potentially replace multiple sequential testing methods and its high-resolution, gene-level detail that is equivalent to high-resolution karyotyping and CMA.
Dr. Levy also highlighted OGM’s potential to eliminate the need for specialized, trained cytogenetic technologists, which are in comparatively short supply relative to demand.
Presentation No. 3
Roger E. Stevenson | Senior Clinical Geneticist | Equanimitas
Dr. Stevenson presented findings from a two-phase multisite study on postnatal constitutional disorders such as intellectual disability, autism, and birth defects in males and females. The study showed that OGM technology is able to detect all classes of SVs and has a high level of concordance with current standard-of-care methods.
The study included samples where OGM was able to detect pathogenic variants missed by standard-of-care methods. Dr. Stevenson concluded by recommending that OGM be considered as a first-tier test for postnatal NND or any case suspected of genetic disease. In his own words:
“I think we should recognize and promote the idea that OGM is a single platform, a single cytogenomic platform that can detect all classes of structural variants in the genome.”
Presentation No. 4
Anja Kovanda, PhD | Assistant Professor | Clinical Institute of Genomic Medicine, University Medica Center Ljubljana, Slovenia
Dr. Kovanda presented on the use of OGM in her lab as a replacement for traditional methods such as Southern Blot. She discussed how OGM’s higher resolution and ease of implementation allowed for faster and more conclusive findings in instances where Southern Blot was inconclusive or required additional testing.
She also presented data demonstrating how OGM followed by panel exome sequencing was more reliable and accurate for classifying FSHD samples than traditional methods.
Dr. Kovanda discussed potential applications of OGM such as validation of NGS, microarray and cyto results, trio analysis for rare samples, and integration into WGS data. Dr. Kovanda reported she was very satisfied with the outcome and eager to apply OGM to additional projects at her institution.
Presentation No. 5
Avinash V. Dharmadhikari, MS, PhD, DABMGG, FACMG | Assistant Director, Center for Personalized Medicine | Assistant Professor of Clinical Pathology – Department of Pathology and Laboratory Medicine, Children’s Hospital of Los Angeles | Keck School of Medicine of the University of Southern California
Dr. Dharmadhikari presented a study that aimed to determine if OGM can improve the interpretation of copy number gains compared to CMA. The study identified 19 unique cases with 20 different copy number gains that were originally classified as “variants of unknown significance” (VUSs) by CMA. The study found that OGM detected all of the copy number gains detected by CMA and also determined their location and structure.
Dr. Dharmadhikari presented several examples to illustrate how OGM provided more detailed and accurate information than CMA, that may have changed the interpretation of some VUSs from uncertain to clinically relevant or benign.
Presentation No. 6
Bárbara Fernández Garoz | Cytogenetic Laboratory Specialist | Niño Jesús Hospital
Dr. Garoz presented a summary of her team’s recent validation activities and experiences with OGM in their lab. She discussed the benefits of OGM, such as its high resolution and elimination of technical subjectivity, as well as its limitations, including its inability to detect mosaicism and certain chromosomal abnormalities.
She presented validation data comparing OGM to karyotyping, arrayCGH, FISH, and Fragile X testing, showing high levels of concordance between OGM and these standard-of-care methods. She also discussed the practical implementation benefits of OGM in her lab.
In characterizing the impact OGM has had on her team’s lab operation, Dr. Garoz reported that they’ve been able to “unify these four techniques [karyotype, arrayCGH, FISH, and Fragile X] into one.”
Presentation No. 7
Alexander Hoischen | Associate Professor Genomic Technologies & Immuno-Genomics | Radboud University Medical Center, Departments of Human Genetics and Internal Medicine
Dr. Hoischen presented data and findings on the use of OGM’s unbiased genome-wide approach for rare disease investigation with trio analysis. He also presented data to support his assertion that OGM is a next-generation cytogenomics platform and should be a tool for the analysis of complex samples from hematological malignancies as well as constitutional genetic disorders.
Some notable lines from his presentation include:
“One can envision OGM to become a generic assay for around 50 well-established repeat expansion loci in the human genome of clinical relevance instead of assay-by-assay development.”
“OGM can replace a number of cytogenetic assays.”
Dr. Hoischen also discussed the potential for OGM to replace cytogenetic technologies, become the standard QC method for cell culturing, and replace all MLPA kits. He also discussed the design of a consortium study using trio testing by OGM to determine de novo SVs and candidate genes in unsolved rare diseases and presented initial summary data from the study.
Lastly, Dr. Hoischen introduced an EU flagship project for unsolved rare diseases (SOLVE-RD) and presented data on how OGM data can be combined effectively with long-read NGS.
Presentation No. 8
Detlef Trost, PhD | Laboratoires CERBA
Dr. Trost presented a study on the application of OGM in unresolved trios with negative exome and array results. The study aimed to investigate unsolved samples using OGM to detect rare variants and known pathogenic genes, and then correlate them with phenotype.
Dr. Trost highlighted examples where OGM was able to detect deletions and duplications affecting exon 1 and the 5′ UTR regions of specific genes that were not detected by array or exome sequencing. He concluded that OGM’s high resolution is able to identify SVs that are not detected by other methods, resulting in a significant increase in valuable insights for these samples. Additionally, he showed that OGM and exome sequencing could be used to identify composite heterozygous situations.
Presentation No. 9
Isabelle Schrauwen | Assistant Professor | Columbia University
Dr. Schrauwen discussed the challenges of investigating neurodevelopmental disorders (NDDs) with current sequencing techniques and the concept of “genomic dark matter,” which refers to regions of the genome that are not well understood due to technological limitations.
She presented OGM as a potential solution for investigating challenging samples and presented data from a study with unresolved NDDs using OGM with de novo assembly, CNV calling, and targeted long-read sequencing. The study found that most of the SVs called were insertions, 14% had pathogenic SVs missed by exome sequencing or microarray, and also revealed rare and unique SVs in novel candidate genes.
Dr. Schrauwen also presented examples of misses that were able to be uncovered by OGM, including insertions, single or partial exon CNVs, and inversions. She concluded that OGM not only improves molecular analysis but also reveals novel NDD genes that may harbor complex variations often missed by standard sequencing techniques.
Learn more about enhancing and streamlining the detection of all classes of structural variants in prenatal and postnatal constitutional genetic disease samples by integrating OGM into your lab.
Register now to join us live this week and view recorded sessions after 1/26/23 on the Bionano Symposium 2023 virtual event platform.
