Unlocking the Unexplored Depths of Genome to Bolster Clinical Research Around Many Complex Diseases

GeneDx, a leader in genetic testing for rare diseases, has officially confirmed the adoption of Illumina’s emerging constellation mapped read technology.

According to certain reports, the company will leverage this particular piece of technology to evaluate its performance on regions of the genome that traditional short-read technologies have, thus far, failed to resolve. As for the early results, they include a quicker identification of hard-to-detect variants implicated in rare disease.

More on that would reveal how, for the pilot project, GeneDx banked upon its fleet of NovaSeq X Plus Systems with constellation kits to assess 160 DNA samples from individuals with known genetic disease. This involves comparison of samples running on constellation against the ones running on orthogonal methods, like long-read sequencing, arrays, and multiplex ligation-dependent probe amplification.

Once that part was over, it was confirmed that constellation can accurately uncover repeat expansions, complex structural variants, and elusive regions of the genome, showcasing an ability to meet or exceed the capabilities of established alternative methods.

“Illumina is unlocking ways to access the most difficult regions of the genome, as we simultaneously lead the industry into a new era of multiomics,” said Steve Barnard, chief technology officer of Illumina. “Genomic insights remain critical to advance diagnosis and treatment for many rare and complex diseases, and our constellation technology provides the research insights that enable our customers to tackle these challenging conditions on the platforms they already use.”

Talk about the whole exercise on a slightly deeper level, constellation was able to quickly identify difficult-to-detect, biologically relevant variants across four archetypes..

The first variant here was markedly associated with DMPK, which relates to myotonic dystrophy and is caused by large repeat expansions.

The next variant in line is of SMN1, typically enjoying strong associations with spinal muscular atrophy. This particular variant has also been difficult to detect based on the highly homologous SMN2 gene.

Another detail worth a mention here is rooted in NCF1, which is associated with an inherited immune disorder called chronic granulomatous disease. The said variant, on its part, has proven challenging to identify because of highly homologous pseudogenes

The fourth variant coming into play would be Mosaic aneuploidy. Mosaic aneuploidy basically causes some cells to have chromosomal abnormalities. As a result, it can cause developmental delays, and at the same time, increase the risk of some childhood cancers.

The development in question further complements Illumina’s industry-leading sequencing-by-synthesis chemistry. You see, these long sequences of unfragmented DNA are basically applied directly to the flow cell for cluster generation.

Such on-flow-cell library prep, like you can guess, treads up a long way to eliminate manual library preparation, while simultaneously facilitating a streamlined workflow with fewer validation steps.

 Alongside that, we have proprietary informatics that effectively extract long-distance data from the proximity of resulting neighboring clusters, eventually producing accurate mapping of homologous or repetitive regions of the genome to resolve mapping ambiguities and simplify complex variant types.

“Innovation and patient centricity fuel everything we do at GeneDx,” said Joe Devaney, GeneDx’s Director of Laboratory Innovation.  “We’re continually looking to advance research and clinical genomics to drive the future of precision medicine and better health outcomes for all. The level of detail we can achieve with constellation provides promising insight into some of the world’s most complex and difficult-to-diagnose diseases. By combining speed, simplicity, and scientific rigor, this technology has the potential to transform how we understand rare disease, helping improve how we diagnose and treat patients.”

• By Editorial Panel
• 09 May 2025