‘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 theAmerican 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."

About Geisinger

Geisinger is among the nation's leading providers of value-based care, serving 1.2 million people in urban and rural communities across central and northeastern Pennsylvania. Founded in 1915 by philanthropist Abigail Geisinger, the nonprofit system generates more than $8 billion in annual revenues across 163 care sites - including 10 hospital campuses - and Geisinger Health Plan, with more than half a million members in commercial and government plans. Geisinger College of Health Sciences educates more than 5,000 medical professionals annually and is conducting more than 1,400 clinical research studies. With more than 27,000 employees, including 1,800 employed physicians and 5,200 registered nurses, Geisinger is among Pennsylvania's largest employers, having an estimated economic impact of $16.8 billion on the state's economy. In 2024, Geisinger joined Risant Health, a nonprofit charitable organization created to expand and accelerate value-based care across the country. Learn more at geisinger.org or follow on Facebook, Instagram and LinkedIn.