Genetic Tests to Speed Diagnosis of Lymphatic Disorders

Defects in the lymphatic system affect approximately one in every 3,500 newborns and can lead to severe complications, including organ failure, breathing difficulties, and life-threatening infections. However, many patients wait years for an accurate diagnosis because lymphatic disorders are often misidentified or lack known genetic causes. Now, a collaborative initiative aims to accelerate diagnosis by developing comprehensive genetic tests for congenital lymphatic diseases.

The initiative, known as CLARUM (Comprehensive Lymphatic Anomaly Revealing and Understanding Genomics), is led by Columbia University Vagelos College of Physicians and Surgeons (New York, NY, USA) and supported by a two-year USD 8.7 million contract from the Advanced Research Projects Agency for Health (ARPA-H) through its LIGHT program. The goal is to identify new genetic mutations responsible for lymphatic anomalies and develop two clinical genetic panels capable of screening for germline and mosaic mutations across 73 known genes associated with primary lymphatic diseases.

Image: In people born with lymphatic system disorders, too many vessels (outlined in green) are created for the lymphatic system (Photo courtesy of Carrie Shawber)

CLARUM will analyze genetic data from 2,000 patients across multiple centers to discover at least 15 new causative mutations. The team will apply advanced bioinformatics tools to identify novel genes, while also using cell-based and zebrafish models to assess variants of uncertain significance. The project also aims to develop methods to detect mosaic mutations before birth, potentially preventing ineffective or harmful treatments in fetuses with cystic lymphatic malformations.

By shortening the time to genetic diagnosis from years to weeks, the project could enable faster access to FDA-approved targeted therapies. Currently, only 20% to 30% of patients with identified mutations benefit from mutation-specific treatments. Expanding the number of known genetic causes may significantly broaden treatment eligibility. By working with technology ventures programs, the team aims to commercialize the genetic panels for use across the US, increasing access beyond major urban medical centers.

“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,” said associate professor Carrie Shawber, PhD, principal investigator of the CLARUM project.

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Vagelos College of Physicians and Surgeons