Illumina, Inc. announced that GeneDx, a leader in genetic testing for rare diseases, is piloting Illumina’s emerging Constellation mapped read technology, aimed at improving resolution in genomic regions that traditional short-read sequencing has struggled to analyze.
Early findings from GeneDx demonstrate Constellation’s ability to rapidly and accurately detect complex and hard-to-find genetic variants implicated in rare diseases. These results were presented by Joe Devaney, Director of Laboratory Innovation at GeneDx, during the American Society for Human Genetics (ASHG) Annual Meeting in Boston.
“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 at 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.”
Pilot Study Highlights
For this pilot project, GeneDx utilized its NovaSeq X Plus Systems with Constellation kits to sequence 160 DNA samples from individuals with known genetic diseases. Results were benchmarked against orthogonal methods, including long-read sequencing, arrays, and multiplex ligation-dependent probe amplification (MLPA).
Constellation successfully identified repeat expansions, complex structural variants, and difficult genomic regions, showing performance comparable to or better than existing methods. Notably, the technology detected variants in:
DMPK – associated with myotonic dystrophy, caused by large repeat expansions.
SMN1 – linked to spinal muscular atrophy, often challenging to distinguish from the homologous SMN2 gene.
NCF1 – tied to chronic granulomatous disease, complicated by the presence of pseudogenes.
Mosaic aneuploidy – involving chromosomal abnormalities that can cause developmental delays and elevate childhood cancer risk.
Advancing Precision Genomics
By delivering deep, rapid whole-genome insights, Constellation supports the identification of potential treatments for rare and complex conditions. The platform is designed to work reliably across multiple sample types—including buccal, blood, and chorionic villus (prenatal) samples—and various extraction kits.
“Innovation and patient centricity fuel everything we do at GeneDx,” said Joe Devaney. “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.”
Inside the Constellation Technology
Constellation builds upon Illumina’s sequencing-by-synthesis chemistry to enable long-range genomic analysis with streamlined simplicity. Long, unfragmented DNA molecules are applied directly to the flow cell for cluster generation, eliminating manual library preparation and minimizing validation steps. Proprietary informatics then extract long-distance genomic information from neighboring clusters, improving mapping accuracy in homologous or repetitive regions and resolving complex variant types.
First introduced at the 2024 ASHG conference, the first commercial product based on Constellation technology is expected to launch in the first half of 2026, compatible with the NovaSeq X Series.
Devaney presented findings from the expanded 160-sample study during his ASHG session titled “Mapping the Future of Whole Genome Sequencing with Illumina Constellation Technology,” held on October 15 in Room 153ABC from 12:00 PM to 1:00 PM ET.
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