Optical genome mapping (OGM) can identify clinically significant genetic variants in a fifth of patients with acute leukemia cases that standard tests have missed, a study has shown.
The genome-wide profiling approach could add value to standard-of-care tests, identifying genetic abnormalities in patients initially reported as normal or for whom standard testing had failed.
This could lead to better selection of therapies and greater accuracy in predicting patient outcomes, the findings in the Journal of Medical Diagnostics suggest.
OGM identified genetic changes across the spectrum of size and complexity, overcoming limitations in resolution and scope found with conventional testing.
“We analyzed the yield of this test in the first 200 patients and found that OGM offered remarkable utility, refining diagnosis or risk stratification in nearly 20% of cases by identifying critical genetic variants that were otherwise missed by traditional workflows,” said lead investigator Tara Spence, PhD, from the University of British Columbia.
OGM enables direct visualization of small and large structural variants based on fluorescent label patterns along ultralong DNA molecules.
DNA is labeled at the CTTAAG sequence motif throughout the genome and linearized in nanochannels on a microfluidic chip. This is imaged and assembled into digital maps that are aligned to a reference genome for the precise identification of genomic alterations.
In November 2023, the researchers implemented OGM as a first-line standard-of-care test for adults with newly diagnosed acute leukemias at their tertiary medical center.
OGM showed robust analytical performance, reproducibility, and limits of detection in validation tests, with 100% specificity, 96.1% sensitivity, and 98.0% accuracy.
Among the first 200 patients with acute leukemia in whom it was used after official implementation, OGM demonstrated 100.0% specificity, 95.6% sensitivity, and 97.3% accuracy, consistent with the earlier tests.
It identified over 640 clinically reportable genetic variants, of which 25% were classified as tier 1A on the basis of clinical significance, 3% as tier 1B, 2% as tier 2, and 70% as tier 3A.
This compared with just 444 that were detected by standard-of-care testing, using a combination of karyotype, fluorescence in situ hybridization (FISH), and panel-based next-generation sequencing.
When used alongside current standard-of-care tests, OGM added clinical value, impacting 35 cases (18%) overall by altering diagnostic classification in 12 and/or risk stratification in 31.
The researchers acknowledge that the longer turnaround for OGM prevents it from fully replacing karyotyping for acute leukemia. Whereas preliminary karyotype reporting took no average two days, preliminary reporting for OGM took nine days on average, with final reporting averaging 13 days.
Nonetheless, they suggest that the high diagnostic yield of OGM justifies its uses as a complementary tool.
“This advanced clinical diagnostic technology offers the opportunity to meaningfully impact the individuals we serve, shedding light on genetic abnormalities that we previously could not visualize due to its incredibly refined resolution for detection of copy number and structural abnormalities,” said Spence.
“It is poised to guide treatment decisions and refine our understanding of expected outcomes.”
