Genomic-First Approach Identifies Rare Genetic Disorders Earlier

Rare genetic disorders (RGDs) affect more than 24 million people in the US, yet many cases remain undiagnosed due to the limitations of traditional testing methods. Current diagnosis typically follows a “phenotype-first” approach, where patients are referred for genetic testing only after clinical symptoms appear, leaving those with mild or no symptoms overlooked. Now, a new study has demonstrated that a genomic-first screening strategy—identifying variants first, then seeking symptoms—can identify these disorders earlier and more effectively than symptom-based testing.

Researchers at the Geisinger Health System (Danville, PA, USA) have developed a large-scale genomic screening framework to identify rare genetic disorders in a healthcare-based population. The team created a database of 2,701 rare diseases that are not routinely screened at the population level and analyzed genetic data from 218,680 participants in Geisinger’s MyCode Community Health Initiative. Automated methods were then applied to match participants’ genomic findings with clinical diagnoses recorded in their electronic health records.

The findings, published in the American Journal of Human Genetics, revealed that 2.5% of participants carried high-confidence genetic variants associated with a rare disorder. Importantly, most of these individuals had no corresponding clinical diagnosis documented in their health records. This finding indicates that the genomic-first approach can uncover previously undetected cases, offering a more accurate estimate of disease prevalence and identifying individuals who might otherwise go undiagnosed.

The study suggests that using genomic data proactively—rather than waiting for clinical symptoms—can enable earlier detection, more precise management, and potentially improved outcomes for patients. It also suggests that the chance of getting sick from these genetic changes may be lower than previously thought. The researchers emphasize that genomic-first programs could reshape healthcare by integrating genetics into preventive and diagnostic practices at scale for a more accurate description of RGD symptoms.

“This important finding suggests that using a genomic-first approach can identify many more people with rare disorders earlier and may also mean that the chance of getting sick from these genetic changes is lower than previously thought,” said Kyle Retterer, MS, senior author of the study. “Using a genomic-first approach offers the potential for earlier and more precise diagnosis, improved management and treatment, and a more accurate description of the symptoms of rare genetic disorders, all of which could contribute to improved outcomes.”

Related Links:
Geisinger Health System