byGeisinger Health System

Graphical abstract. Credit:The American Journal of Human Genetics(2025). DOI: 10.1016/j.ajhg.2025.09.010

A "genomic-first" approach to screening for rare genetic disorders—identifying specific genetic variants and then studying associated traits and symptoms—can identify these conditions earlier and more frequently than standard genetic testing driven by clinical symptoms, a Geisinger study found.

Rare genetic disorders (RGD) affect at least 24 million people in the United States, or more than 5% of the total population. Diagnosis of RGD has historically resulted from a "phenotype-first" approach, in which people with clinical symptoms are referred for genetic testing to identify an underlying cause. This approach can underestimate the prevalence of RGD, as people with less severe symptoms, or no symptoms at all, are less frequently referred forgenetic testing.

For their study, the Geisinger team developed a list of 2,701 RGDs that are not routinely screened at the population level and then created a strategy for identifying disease-causing variants in this gene list within a group of 218,680 participants in Geisinger's MyCode Community Health Initiative.

The research team developed and applied automated methods for comparing participants' genomic findings to existing clinical diagnoses, which they defined as "diagnostic fit" (DxFit). They discovered that 2.5% of this group had a high-confidencegenetic changefor an RGD, but the DxFit assessment revealed that the majority of these people did not have evidence of a corresponding clinicaldiagnosisin their electronic health record.

The study was published online this week inThe American Journal of Human Genetics.

"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, chief data science officer at Geisinger and 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 ofrare genetic disorders, all of which could contribute to improved outcomes."

More information: Rebecca I. Torene et al, A scalable approach for genomic-first rare disorder detection in a healthcare-based population, The American Journal of Human Genetics (2025). DOI: 10.1016/j.ajhg.2025.09.010 Journal information: American Journal of Human Genetics

Provided by Geisinger Health System