‘Genomic-first’ approach can identify rare genetic disorders earlier

DANVILLE, Pa. – 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 for genetic 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-confidence genetic change for an RGD, but the DxFit assessment revealed that the majority of these people did not have evidence of a corresponding clinical diagnosis in their electronic health record.

The study was published online this week in the 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 of rare genetic disorders, all of which could contribute to improved outcomes.”

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About Geisinger College of Health Sciences

Geisinger College of Health Sciences is the research and education arm of the Geisinger family. Geisinger is committed to making better health easier for the more than 1 million people it serves. Geisinger is the inaugural member of Risant Health, a nonprofit dedicated to expanding and accelerating the adoption of value-based care. Founded more than 100 years ago by Abigail Geisinger, the system now includes 10 hospital campuses, a health plan with more than half a million members, and the College. The College houses a Research Institute, graduate medical education, and schools of medicine, nursing and graduate education, in addition to faculty and professional development programs. The College is committed to non-discrimination in all employment and educational opportunities. Visit geisinger.edu/gchs.