ABOVE: Fluorescently labeled DNA used to create an optical genome map

Genome maps provide an overall view of major variations in a person’s chromosomes, such as big insertions or deletions or the 180-degree flipping of sequences. Some of these structural variants are associated with genetic predispositions to diseases. For instance, many blood cancers are linked to chromosomal rearrangements in which parts of a chromosome break and then attach to another chromosome. 

Maps of those rearrangements and other structural variations in chromosomes are currently derived from a multitude of tests, but according to the authors of a pair of studies published online July 7 in the American Journal of Human Genetics, only one is needed: a method known as optical genome mapping. This technique uses fluorescence microscopy to visualize the structure of DNA molecules, which in aggregate provides an overall map of a genome’s structure. In their studies, a single optical map could detect disease-relevant structural variants previously identified by one or more of three established mapping tools. The researchers say that this single test, initially developed by David Schwartz of New York University in the 1990s, could eventually displace all the others. 

“We proved that known aberrations are faithfully detected by the [optical genome mapping] technique,” says senior author Laïla El-Khattabi, a cytogeneticist at the Institut Cochin in Paris. The next step, El-Khattabi says, is to compare the accuracy of optical genome mapping to the established tools when the aberrations are not known in advance. If the optical genome map holds its own against other techniques, or finds more complexity in the aberrations than was detectable otherwise, it could become the go-to test for clinicians. 

See “Chromosomal Instability Drives Cancer Metastasis

One of the appeals of optical genome mapping is that the older techniques—especially one called karyotyping, which produces photographs of stained chromosomes in a sample—require specialized training and expertise, says Alexander Hoischen, a geneticist at Radboud University Medical Center in the Netherlands who collaborated with El-Khattabi. The goal of the karyotype test is to identify chromosomes that appear abnormally long or unusually shaped, an interpretative process that Hoischen notes is somewhat subjective. 

“Karyotyping is almost an art,” he says, whereas in his view preparing and analyzing optical genome maps would be more automated and objective.

One of the two studies, led by Hoischen and El-Khattabi, focused on “constitutional” structural variants that people are born with and that are linked to developmental or reproductive disorders. The team used optical genome mapping to examine blood samples or cultured cells for 99 total chromosomal variants derived from 85 patient samples. The variants had previously been detected by karyotyping or two other tests: FISH, an earlier technique for detecting structural variation that also uses fluorescent microscopy but that might miss some types of structural variation, or a copy number variant assay, which uses a microarray to detect varying numbers of copies of a gene between one person and another. In every case, an optical genome map found the previously detected aberrations. The other tests had each only detected a subset of these variants.

The other study, led by Hoischen, focused on chromosomal aberrations linked to blood cancers such as acute myeloid leukemia. These generally build throughout a person’s lifetime. In 50 of 52 cases, the optical genome map detected the same variations as the standard tests did. The optical mapping method additionally identified more complex chromosomal structures that the other tests had missed, which the authors say could eventually inform clinical care decisions, though further studies are needed to link these variants to specific manifestations of blood cancer.

“I hope that more and more groups will follow us and show that it works this way,” Hoischen says.

Rashmi Kanagal-Shamanna, a pathologist who diagnoses blood cancer at the MD Anderson Cancer Center in Houston and who was not involved in the studies, says she is excited about a potential shift toward optical genome mapping as a primary diagnostic technique due to its ability to detect structural abnormalities that might not be detected otherwise. Sometimes this information can drive clinical care decisions today, she says, while in other cases it’s fodder for further research. 

She notes, however, that standard karyotyping methods provide useful diagnostic information at a reasonable cost and are currently very embedded in diagnostic protocols for blood cancers. Therefore, any move away from karyotyping should only occur after extensive further validation that optical genome mapping works, she says.

“What I’m excited about is actually standardizing care,” says Brynn Levy, a professor of pathology and cell biology at the Columbia University Medical Center who also not involved in either study. Levy agrees with Hoischen that interpreting karyotypes is somewhat subjective and additionally points out that the quality of a karyotype is dependent on the equipment available at a given medical center—and in some cases, the necessary equipment isn’t available at all. In contrast, optical genome mapping relies on standard molecular visualization tools that Levy says he believes could be set up with relative ease in most parts of the world.