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January 25, 2025
Researchers at UC Santa Cruz revolutionize genetic testing, drastically reducing diagnosis time and cost for rare diseases.
One in every 10 people worldwide is affected by a rare genetic disease. However, half of them remain undiagnosed due to limitations in current genetic testing methods. The journey to a diagnosis can take years—often far too late to begin timely treatments. Yet, cutting-edge research by UC Santa Cruz’s Genomics Institute is offering new hope for these patients, especially children, by reducing the time and cost associated with diagnosing rare diseases through a breakthrough in sequencing technology.
The research, recently published in The American Journal of Human Genetics, demonstrates the power of long-read sequencing, an innovative method that allows scientists to gather a more comprehensive genetic dataset and access previously inaccessible regions of the genome. This technology offers the promise of diagnosing rare diseases in days instead of years—and at a fraction of the cost of current clinical methods.
The Problem with Current Testing Methods
At present, the most commonly used technique for genetic testing in clinical settings is short-read sequencing, which reads small sections of the genome, typically between 150 to 250 base pairs. While short-read sequencing has proven useful in many cases, it is limited in its ability to detect genetic variants in more complex regions of the genome. Additionally, it does not offer “phasing” information, which helps determine which genetic variants come from each parent—crucial for accurate diagnoses, especially when parental genetic data is unavailable.
The Power of Long-Read Sequencing
Long-read sequencing, on the other hand, reads much longer stretches of DNA in a single pass, providing a more complete picture of an individual’s genome. This approach can not only identify more genetic variations but also capture crucial phasing data and even methylation patterns—chemical signals that control gene expression and can be linked to disease.
The UC Santa Cruz team, led by Professor Benedict Paten, Associate Professor Karen Miga, and former postdoctoral scholar Jean Monlong, used nanopore sequencing technology to perform long-read sequencing on 42 patients with rare diseases. The results were groundbreaking.
Successes in Rare Disease Diagnosis
In a cohort of 42 patients, 11 received conclusive diagnoses thanks to long-read sequencing, including patients with congenital adrenal hypoplasia, disorders of sex development, and neurodevelopmental disorders. The sequencing revealed additional rare variants, long-range phasing, and methylation data that short-read sequencing had missed, enabling a clearer, more accurate diagnosis in just a matter of days.
For instance, long-read sequencing successfully solved cases of congenital adrenal hypoplasia, a rare condition that affects the adrenal glands. The gene responsible for this disorder is in a region of the genome that short-read sequencing technology cannot properly assess. The researchers were also able to resolve several other long-standing diagnostic mysteries, offering much-needed answers for families who had been struggling with undiagnosed conditions for years.
A Bright Future for Rare Disease Diagnostics
This breakthrough in genetic sequencing could revolutionize the way rare diseases are diagnosed. Currently, the process can take years and involve multiple specialized tests. Long-read sequencing reduces the need for these lengthy diagnostic journeys, potentially transforming what has traditionally been a long and frustrating process into one that can be completed in a matter of hours.
“Long-read sequencing is likely the next best test for unsolved cases with either compelling variants in a single gene or a clear phenotype,” said Shloka Negi, a Ph.D. student and first author of the study. “It can serve as a single diagnostic test, reducing the need for multiple clinical visits and transforming a years-long diagnostic journey into a matter of hours.”
With its ability to unlock previously inaccessible regions of the genome, long-read sequencing is set to change the landscape of genetic testing for rare diseases. Researchers are hopeful that as the technology advances, it will become a standard tool in clinical settings, helping to solve even more complex and challenging cases.
Looking Ahead
While the long-read sequencing data is promising, scientists acknowledge that it will take time to fully interpret the vast amount of new information it provides. The integration of these findings into clinical practice and databases will be a gradual process, but the potential benefits for patients—especially those with rare diseases—are undeniable.
The research team at UC Santa Cruz is already working on optimizing long-read sequencing methods and collaborating with clinicians to test the technology in real-world settings. As they continue to refine these techniques, they hope to expand their work to a broader range of genetic conditions and ultimately improve the lives of countless individuals who suffer from undiagnosed rare diseases.
Disclaimer: The findings in this article are based on research from UC Santa Cruz’s Genomics Institute. The study is ongoing, and while long-read sequencing shows significant promise, further research and validation are required before widespread clinical implementation. Always consult a medical professional for diagnosis and treatment options.
