$8.7 Million ARPA-H Contract Targets Faster Genetic Diagnosis of Lymphatic Disorders

About one in every 3,500 babies is born with a defect in the lymphatic system, the network of vessels, ducts, and nodes that moves fluid throughout the body, supports immune function, and prevents organ damage. Many require intensive care immediately after birth. Yet a vast majority of these patients - researchers estimate close to 80% - are never correctly identified, receiving wrong diagnoses or no diagnosis at all, particularly in rural areas where specialized genetic testing is unavailable.

A new $8.7 million, two-year contract from the Advanced Research Projects Agency for Health (ARPA-H) is designed to change that. The funds go to a six-institution consortium called CLARUM - Comprehensive Lymphatic Anomaly Revealing and Understanding Genomics - led by Carrie Shawber, PhD, at Columbia University Vagelos College of Physicians and Surgeons.

Why Lymphatic Diseases Are So Often Missed

The lymphatic system is poorly understood by the public and, historically, underexplored by researchers compared to the cardiovascular or nervous systems. Its problems are easily confused with other conditions. Lymphatic diseases present with symptoms as varied as breathing difficulties caused by swelling around the lungs, increased vulnerability to severe infections, and progressive organ damage that worsens as patients age.

A genetic diagnosis can accelerate treatment significantly. In the roughly 20-30% of cases where a specific genetic mutation can be identified, targeted therapies exist that have produced meaningful improvements. "Since the first genes that cause lymphatic disease were identified about a decade ago, three therapies have been identified and those patients are responding very well to the treatments," said Shawber. "Genetics research has changed the landscape of treatment for lymphatic anomalies, but it hasn't gone far enough yet to help the majority of patients."

The problem is that most cases cannot currently be attributed to a known genetic cause. The genes responsible for the majority of congenital lymphatic disease remain unidentified.

What CLARUM Plans to Accomplish

The project brings together Arkansas Children's Hospital, Boston Children's Hospital, the Broad Institute, Children's Hospital of Philadelphia (CHOP), City St. George's University of London, and NYU Langone Health. Together they will study 2,000 patients - a scale that no single institution could achieve alone, given how rare these conditions are.

Shawber expects the consortium to identify 15 or more new genetic mutations that cause lymphatic disease. The team will then develop two comprehensive genetic panels that screen for both germline mutations (inherited) and mosaic mutations (present in only some cells) in 73 genes associated with primary lymphatic anomalies. CHOP and Columbia will develop the panels in parallel, then work with their technology ventures programs to commercialize them for nationwide clinical use.

Current genetic testing is concentrated at a few specialized centers in large urban hospitals. "A problem with genetic testing today is that patients in rural America don't have access to these tests, and so they're not diagnosed or treated appropriately," Shawber said. The CLARUM panels are being designed for specimens generated by standard clinical care, making them usable by doctors' offices across the country without specialized laboratory infrastructure.

From Variants of Uncertain Significance to Clinical Answers

A specific challenge in genetic diagnosis is that many identified mutations are classified as variants of uncertain significance - the sequence is unusual, but there is not enough evidence yet to confirm it causes disease. NYU Langone, City St. George's, and Columbia will develop cell-based and zebrafish-based models to rapidly test whether uncertain variants are actually disease-causing. Zebrafish are particularly useful for this purpose because they can be genetically modified quickly and their transparent embryos allow researchers to observe lymphatic development directly.

Another aim is to detect mosaic mutations before birth in fetuses with cystic lymphatic malformations. Identifying a mutation prenatally could prevent these fetuses from receiving treatments that are ineffective for their specific genetic subtype while they await a definitive genetic diagnosis.

The Diagnostic Timeline Transformation

The current diagnostic journey for lymphatic anomaly patients typically spans years. Patients cycle through multiple specialists before the correct diagnosis is made, during which time they may receive treatments that don't target their actual condition. The CLARUM team aims to reduce the time from specimen collection to genetic diagnosis from years to weeks, which would accelerate access to the small number of FDA-approved therapies that target specific mutated genes.

The funding comes from ARPA-H's LIGHT program - Lymphatic Imaging, Genomics, and pHenotyping Technologies - which is specifically designed to advance diagnostic approaches for conditions involving the lymphatic system.