“Discovering genes that cause lymphatic anomalies and using this information to create new clinical tests will not only accelerate the diagnosis of patients, but will also lead to improved treatments and, most importantly, save lives,” says Carrie Shawber, PhD, associate professor of reproductive sciences at VP&S and principal investigator of the CLARUM (Comprehensive Lymphatic Anomaly Revealing and Understanding Genomics) project.
CLARUM includes collaborators at 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.
The funding is provided by the ARPA-H LIGHT (Lymphatic Imaging, Genomics, and pHenotyping Technologies) program, which aims to illuminate the unseen aspects of the lymphatic system through novel diagnostic approaches and significantly improve patient care and outcomes by gaining a deeper understanding of its critical role in health.
What is the lymphatic system? Most people have heard about their lymph nodes, which are often inflamed during infections, but are less familiar with the rest of their lymphatic system.
Sometimes called the “forgotten circulation,” the lymphatic system is a network of vessels, ducts, and nodes that moves fluid throughout the body, ensuring that tissues maintain normal fluid levels and that fats, hormones, and immune cells reach their destinations. The lymphatic system also prevents organ damage and promotes organ regeneration.
What are congenital lymphatic diseases? Defects in the lymphatic system can disturb the flow of this liquid (called lymph) and cause a variety of serious health problems, from trouble breathing caused by swelling around the lungs to increased vulnerability to severe infections.
Approximately one in every 3,500 babies is born with a lymphatic defect and often requires intensive care soon after birth. Many people with lymphatic anomalies die from sepsis because they cannot mount an immune response to infections.
Severe lifelong consequences from the defects continue to accumulate as the patients age.
In many cases of lymphatic anomalies, the lymphatic system continues to grow abnormally, affecting every organ. “The growth damages the organs and eventually causes organ failure, particularly in the spleen, heart, and lungs,” says Shawber.
The CLARUM project will create better genetic diagnostic tests Lymphatic diseases are often confused with other conditions, and it can take years for some patients to receive the correct diagnosis.
Diagnosis can be sped up by looking for genetic mutations that are known to cause lymphatic diseases. But many genetic causes are yet to be identified, and most cases cannot be attributed to a known genetic cause. Genetic diagnosis is also limited to a few specialized centers in the U.S., primarily in large urban hospitals.
The goal of CLARUM is to develop new genetic tests that can identify more cases of congenital lymphatic disease and can be requested by doctors’ offices across the country.
“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 says. “Because of limited access to testing, it’s thought that we may be missing almost 80% of patients.”
Shawber expects that the CLARUM team will find 15 or more new genetic mutations that cause lymphatic disease and increase the predictive value of genetic testing.
Gene discovery could improve treatment of lymphatic anomalies Today, about 20-30% of patients with lymphatic anomalies caused by specific mutations may be helped by treatments that target those mutations.
“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 and seeing significant improvements in their quality of life,” says 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. So there is a desperate need to identify more genes.”
How the research will be conducted Congenital lymphatic anomalies are rare, and no single medical center sees enough cases to permit robust gene discovery. CLARUM brings together six academic medical centers that will combine forces to look for genes in 2,000 patients.
Columbia and CHOP will develop, in parallel, two comprehensive genetic panels to screen specimens generated by standard clinical care.
The other parts of project will focus on increasing the diagnostic yield of these genetic panels by identifying novel mutations in known and unknown genes.
Arkansas Children’s Hospital, Boston Children’s Hospital, Columbia, and City St. George’s University of London will contribute unique cases, and Broad will apply its advanced genetic bioinformatic pipeline to identify novel genes.
Another challenge is that most mutations identified to date are variants of uncertain significance (VUS), lacking sufficient evidence that they cause disease. NYU Langone, City St. George’s, and Columbia will develop cell- and zebrafish-based models to rapidly screen VUS’s to determine if they are disease-causing.
The Columbia team will also work with collaborators at Broad on developing a robust and reproducible method to detect mosaic mutations before birth, which may prevent fetuses with cystic lymphatic malformations from being treated prior to receiving a genetic diagnosis with potentially ineffective therapies that carry the risk of side effects.
CLARUM aims to develop two different genetic tests that will be ready for clinical use within two years. The tests will use common specimens (tissues and lymph-containing fluids) generated from standard care to detect lymphatic anomalies and simultaneously screen for both germline and mosaic mutations in 73 genes associated with primary lymphatic anomalies. The team aims to shorten the time for genetic diagnosis of lymphatic anomalies from years to weeks, which may speed access to FDA-approved therapies that target mutated genes linked to lymphatic anomalies.
The CHOP and Columbia teams will work closely with their technology ventures programs to commercialize the genetic panels for nationwide clinical use.
“It’s taken decades for us to find and evaluate the mutations that enabled current genetic tests,” says Shawber. “With the help of ARPA-H's LIGHT Program, we can make a substantial leap forward.”
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