New Laboratory Method Speeds Diagnosis of Rare Genetic Disease

Diagnosing genetic immune disorders like Activated-PI3Kδ syndrome (APDS) is often challenging, particularly when genetic testing reveals variants of uncertain significance (VUSs) rather than clearly pathogenic mutations. This diagnostic ambiguity can leave patients without access to targeted therapies like leniolisib—the only approved treatment for APDS. Now, researchers have developed a new laboratory method that can more rapidly determine whether uncertain genetic variants cause APDS, helping patients escape diagnostic uncertainty and gain timely access to care.

The solution was developed by scientists at Columbia University Irving Medical Center (CUIMC, New York, NY, USA), who aimed to improve the functional classification of genetic variants involved in APDS. Their work was recently published in the journal Cell. To develop the new method, the team employed a CRISPR base editor to introduce thousands of mutations into the APDS-related genes. They then evaluated how each genetic variant affected the behavior of healthy human T cells in a laboratory setting. Variants that produced APDS-related changes in the T cells were identified as gain-of-function mutations. These findings enable researchers to flag potentially pathogenic variants for further clinical evaluation and eventual diagnostic classification.

Image: A new laboratory method could help detect rare immune disorders more quickly (Photo courtesy of 123RF)

This method has already demonstrated real-world impact. Informed by the findings, one patient—previously undiagnosed despite symptoms—was confirmed to have APDS and has since begun receiving leniolisib. APDS, caused by mutations in genes essential for immune function, leads to a range of issues, including recurring infections, autoimmune problems, and a heightened cancer risk from an early age. By clarifying uncertain variants, this new method directly enables access to targeted therapy. Encouraged by the success with APDS, the researchers are now adapting this high-throughput functional screening approach to investigate other rare immune diseases. Their method promises to streamline diagnosis for a broader group of patients who currently remain in diagnostic limbo, ultimately accelerating access to treatment and improving clinical outcomes.

“Our findings give physicians a resource that can help them rapidly diagnose and treat patients and avoid cumbersome assays and long diagnostic odysseys that delay treatment,” says study leader Benjamin Izar, the Vivian and Seymour Milstein Family Associate Professor of Medicine. “Beyond rare disorders, these methods could usher in an era of the Human Genome Project Version 2, where we not only describe whether or not a variant exists, but begin to understand whether such genetic variation, either alone or in combination, has an impact on a given phenotype.”