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Team Presents Optical Genome Mapping Method for Finding Chromosomal Alterations

NEW YORK – A team led by investigators at the University of Paris, INSERM, and Radboud University Medical Center has outlined an optical genome mapping, or OGM, method for picking up clinically relevant chromosomal alterations, providing a potential alternative to conventional cytogenetic approaches.

"Optical genome mapping is a kind of all-in-one technique for chromosomal analysis," co-senior and co-corresponding authors Laïla El Khattabi, a cytogenetics researcher at the University of Paris, and Alexander Hoischen, a human genetics researcher at Radboud University, said in an email.

"We foresee that OGM will revolutionize the cytogenetics field," they added, noting that OGM "can offer an objective, automatable and possibly high-throughput alternative."

For their proof-of-principle analyses, published in the American Journal of Human Genetics on Tuesday, the researchers applied OGM to 85 blood or cell culture samples with known chromosomal abnormalities from individuals with hereditary conditions who were previously assessed at centers in France or the Netherlands. There, they uncovered 99 chromosomal changes, ranging from deletions, duplications, insertions, or inversions to translocations and complex rearrangements.

After isolating ultra-high molecular weight DNA from the samples and preparing the samples for OGM with the Bionano Genomics Saphyr instruments, they focused in on structural variants, CNVs, and other chromosomal alterations in de novo genome assemblies, comparing the chromosomal patterns with those identified by conventional methods such as karyotyping, fluorescence in situ hybridization (FISH), and array-based copy number variant (CNV) profiling.

Along with relatively straightforward alterations, the OGM analyses led to complex genetic changes including those linked to repeat-mediated microdeletion/microduplication syndromes, the team reported, touting the approach as an affordable alternative to karyotyping, FISH, and CNV microarrays.

"These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal abnormalities and structural variants, which could give rise to an era of 'next-generation cytogenetics,'" the authors wrote.

In a related paper appearing in AJHG on Tuesday, members of the same team assessed OGM in the hematological malignancy setting, retrospectively using the optical mapping with the Saphyr genome imaging system to search for informative chromosomal changes in 52 hematological malignancy samples from cases diagnosed in the past. That set included three dozen cases with relatively simple cases involving fewer than five chromosomal changes, while 16 cases involved complex chromosomal changes marked by five or more aberrations.

In that setting, the investigators reported, OGM identified more than 900 structural variants, on average, and some 73 CNVs per sample, including all of the structural variants and CNVs identified in the simple sample set in the past. The OGM approach also uncovered some alterations that were even more complex than those previously detected in the complex sample collection.

"Detailed technical comparison with standard-of-care tests showed [the] high analytical validity of OGM, resulting in a sensitivity of 100 percent and a positive predictive value of [more than 80 percent]," the authors reported, adding that the OGM method "resulted in a more complete assessment than any previous single test and most likely reported the most accurate underlying genomic architecture."

Based on these and other findings, the authors suggested that OGM "has the potential to replace existing cytogenetic analyses and may become the one generic test for all (molecular) cytogenetic applications, thereby being highly complementary to existing sequencing-based technologies."

The researchers are now using OGM on newly collected samples, looking at the clinical utility of this approach in a prospective setting, as well as its performance compared to more conventional karyotyping, FISH, and CNV array approaches used individually or in combination with one another. Such studies are expected to boost OGM implementation in workflows for diagnosing genetic conditions, El Khattabi and Hoischen explained.

"We also hope that our work will inspire others to start using OGM," they said, noting that "a broader user base — and in particular a clinical user community — will … push OGM towards clinical and clinical research use."

In a statement from Bionano Genomics, the company's CEO Erik Holmlin added that Bionano "is poised to substantially transform genetic analysis with OGM, and these publications set the baseline for the transformation."