New methods speed diagnosis of rare genetic disease

(Press-News.org) NEW YORK, NY (June 20, 2025)—A new laboratory method developed by researchers at Columbia University Vagelos College of Physicians and Surgeons may now help physicians more quickly diagnose patients with suspected genetic disorders of the immune system, many who have been trapped in diagnostic limbo for years. 

The researchers, who published their findings June 20 in Cell, applied the method to one rare inborn error of immunity called activated-PI3Kδ syndrome (APDS) and found dozens of additional genetic variations that could cause the syndrome.

“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.

“For APDS patients, rapid diagnosis is particularly critical because there is an effective, FDA-approved precision therapy available,” adds Zachary Walsh, an MD/PhD student in the Izar lab who conducted much of the research.

The findings have real-time impact on patients' lives. Guided by the findings from this study, one patient has received a diagnosis of APDS, which causes a wide range of health problems, including infections, autoimmune disease, and increased risk for certain cancers at a young age. This patient is now receiving the precision therapy, a drug called leniolisib, which targets the aberrantly functioning protein.

“And we think there are more patients to find,” Izar says.

Based on the success with APDS, the Columbia researchers, together with colleagues Joshua Milner and Dusan Bogunovic from the Department of Pediatrics at Columbia, are now looking to apply their method to other diseases, starting with other rare immune disorders. 

“There are so many diseases we could do this for, and hopefully it's just the tip of the iceberg,” Walsh says.

 

The problem of ambiguous genetic tests in medicine

The methods developed by the Columbia team were designed to uncover genetic variants that cause APDS, a genetic disease that is caused by specific changes in either of two genes that are vital to the function of immune cells. 

Patients are diagnosed with APDS when genetic testing reveals known APDS-causing variants, which makes patients eligible for leniolisib, the only targeted treatment for APDS. 

But genetic testing isn’t always clear cut. For every variant that's known to cause APDS, there are hundreds of variants of uncertain significance, or VUSs, that have not been classified.

“The problem is we don’t know whether a VUS is relevant to the person’s condition or just reflective of normal differences from one person to another,” Izar says. “They pose a major challenge and create ambiguity on what to do with affected individuals.”

 

New methods help lift genetic uncertainty

To speed the functional evaluation of VUSs in APDS, the Columbia researchers used a CRISPR base editor to make thousands of mutations in the APDS genes and then measured the impact of each of those genetic changes on healthy human T cells in the lab. Variants that caused APDS-related changes in the T cells were classified as gain-of-function, and further clinical observation may enable their classification as pathogenic. 

“What made our study so powerful was our ability to create thousands of variants in the genes, whether they had previously been encountered in patients or not,” says Walsh. “By proactively classifying variants, even before they're found in patients, we hope we can get out ahead of the VUS problem.”

“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”, Izar says. 

 

APDS may be more common than we thought

Only a few hundred Americans are thought to have APDS, but based on a search of hundreds of thousands of genomes, the new study suggests that APDS could be magnitudes of order more common than previously estimated, possibly affecting one in every 10,000 Americans.

The researchers found potential gain-of-function variants in about one of every 5,000 Americans in the All of Us precision medicine program, which has sequenced the genomes of more than 630,000 Americans. Some people who carried the variants had signs and symptoms consistent with APDS recorded in their health records but had not been diagnosed with the syndrome.

“These people may have milder symptoms but could potentially benefit from the new targeted treatment,” Izar says. “Physicians need to be more aware of the syndrome’s signs and symptoms so more patients can undergo genetic testing and be diagnosed.”

“These findings also hint that a lot of ultrarare or rare genetic diseases may be not as rare as we think,” says Walsh. “The framework we developed for APDS could be applied to many other diseases, both rare and more common, to identify more pathogenic variants and more patients, and get a better sense of the true prevalence of these diseases.”

 

More information

All authors (from Columbia University): Zachary H. Walsh, Chris J. Frangieh, Neeharika Kothapalli, Jay Levy, Clarissa K. Heck, Johannes C. Melms, Ron S. Gejman, Parin Shah, Jared M. Pollard, Akul Naik, Sarah L. Grauman, Lei Haley Huang, Ashley Lee, Dusan Bogunovic, Joshua D. Milner, and Benjamin Izar.

This work was supported by Columbia University’s Herbert Irving Comprehensive Cancer Center Human Tissue Immunology and Immunotherapy Initiative and through the NIH/NCI Cancer Center Support Grant P30CA013696. This work was also supported in part through a sponsored research agreement with Pharming; the NIH (grants R37CA258829, R01CA266446, R01CA280414, U54CA274506, F30CA298572); the Burroughs Wellcome Fund Career Award for Medical Scientists; a Velocity Fellows Award; the Louis V. Gerstner Jr. Scholars Program; the Melanoma Research Alliance (Tara Miller Young Investigator Award and Tara Miller Team Science Award for Brain Metastasis Research); a Pershing Square Sohn Cancer Research Alliance Award; and a Melanoma Research Foundation Medical Student Award. Benjamin Izar is a CRI Lloyd J. Old STAR (CRI5579).

Benjamin Izar and Joshua Milner received research support from Pharming. Benjamin Izar is a consultant for or received honoraria from Volastra Therapeutics, Johnson & Johnson/Janssen, Novartis, GSK, Eisai, AstraZeneca and Merck, and has received research funding to Columbia University from Agenus, Alkermes, Arcus Biosciences, Checkmate Pharmaceuticals, Compugen, Immunocore, Regeneron, and Synthekine. Benjamin Izar is the founder of Basima Therapeutics, Inc. Joshua Milner is on the scientific advisory board for Blueprint Medicine and receives grant funding from Pharming. The other authors do not have competing interests.

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Columbia University Irving Medical Center (CUIMC) is a clinical, research, and educational campus located in New York City. Founded in 1928, CUIMC was one of the first academic medical centers established in the United States of America. CUIMC is home to four professional colleges and schools that provide global leadership in scientific research, health and medical education, and patient care including the Vagelos College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing. For more information, please visit cuimc.columbia.edu. 

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