A groundbreaking initiative led by Columbia University Vagelos College of Physicians and Surgeons has recently secured up to $8.7 million in funding from the Advanced Research Projects Agency for Health (ARPA-H). This ambitious project aims to revolutionize the diagnosis of congenital lymphatic system defects through the development of advanced genetic testing tools, potentially transforming patient outcomes and accelerating therapeutic interventions. This initiative, known as the Comprehensive Lymphatic Anomaly Revealing and Understanding Genomics (CLARUM) project, seeks to uncover the genetic underpinnings of lymphatic anomalies and make diagnostic testing widely accessible across diverse healthcare settings.
The lymphatic system, often overshadowed by its cardiovascular counterpart, plays an indispensable role in maintaining homeostasis and immune function. It consists of an intricate network of vessels, ducts, and lymph nodes responsible for transporting lymph—a fluid containing immune cells, hormones, and lipids—throughout the body. Beyond fluid balance, the lymphatic system contributes fundamentally to organ regeneration and defense mechanisms. Despite its critical nature, the lymphatic system remains poorly understood, leading some experts to dub it the “forgotten circulation.”
Congenital lymphatic disorders emerge when genetic defects disrupt the normal flow and function of lymph. These anomalies can cause severe clinical manifestations, including respiratory difficulties due to pulmonary lymphatic malformations and increased susceptibility to life-threatening infections such as sepsis. Statistically, about one in every 3,500 newborns is affected by a congenital lymphatic defect, necessitating prompt and specialized medical care immediately after birth. Unfortunately, many of these patients face grim prognoses, as the disease progression often leads to progressive organ damage and eventual failure.
The genetic architecture of lymphatic anomalies remains incompletely defined, hampering timely diagnosis and targeted treatment. Presently, genetic testing capable of identifying causative mutations is limited to a handful of specialized centers, predominantly clustered in urban academic hospitals. This bottleneck contributes to diagnostic delays of several years, during which patients may receive inappropriate or insufficient care. Through CLARUM, the researchers aim to decode previously unidentified genetic mutations responsible for lymphatic diseases, thereby expanding the repertoire of detectable genetic markers for these conditions.
A central goal of CLARUM is to democratize genetic testing by creating new, clinically deployable panels accessible to physicians nationwide, including those practicing in rural and underserved areas. Carrie Shawber, PhD, principal investigator of the project, highlights the critical gap in current diagnostics, pointing out that up to 80% of patients may remain undiagnosed due to limited testing availability. By integrating next-generation sequencing and bioinformatics, the project anticipates identifying at least 15 novel gene mutations associated with lymphatic dysregulation, enhancing the sensitivity and predictive power of genetic diagnostics.
Therapeutic advances in lymphatic anomalies have been modest but promising. Over the past decade, identification of key genetic mutations has facilitated the development of targeted treatments that benefit approximately 20 to 30 percent of patients. These therapies have significantly improved quality of life for affected individuals. Nevertheless, a majority of patients continue to lack effective treatment options due to insufficient understanding of underlying genetic causes. Thus, discovering additional pathogenic genes is imperative for broadening therapeutic possibilities and improving clinical management.
The execution of CLARUM leverages a multicenter collaborative approach, bringing together six prestigious institutions including Columbia University, Children’s Hospital of Philadelphia, Arkansas Children’s Hospital, Boston Children’s Hospital, City St. George’s University of London, and the Broad Institute. This consortium will collectively analyze genetic material from a cohort of 2,000 patients, ensuring robust data acquisition necessary for sound gene discovery. The dual development of comprehensive genetic panels by Columbia and CHOP will facilitate high-throughput screening of patient specimens obtained via routine clinical procedures.
An important challenge in genetic diagnostics is the characterization of variants of uncertain significance (VUS), which are genetic alterations whose disease-causing potential remains ambiguous. To address this, several collaborators will establish cellular and zebrafish models to functionally validate these variants, accelerating the classification process. Furthermore, the team is advancing methods to detect mosaic mutations—genetic changes that occur post-zygotically and may only affect a subset of cells—before birth. Early detection of such mutations could allow for more precise prenatal interventions, potentially avoiding ineffective treatments with harmful side effects.
By the project’s conclusion, CLARUM aims to deliver two genetic tests ready for clinical use within a two-year timeframe. These assays will simultaneously identify germline and mosaic mutations across 73 genes implicated in primary lymphatic anomalies using common tissue and lymph fluid samples. This innovation promises to dramatically shorten diagnostic timelines from years to mere weeks, enabling earlier access to FDA-approved targeted therapies that could mitigate disease progression and improve survival rates.
Commercialization pathways are actively being developed in concert with Columbia and CHOP’s technology ventures programs to facilitate widespread clinical adoption of these assays. The ultimate vision is to transform the landscape of congenital lymphatic disease management, ushering in an era of precision medicine for patients historically underserved by current genetic testing paradigms. Carrie Shawber emphasizes that while gene discovery in this field has taken decades, the support from ARPA-H’s LIGHT program inaugurates a new epoch defined by rapid innovation and enhanced patient care.
With this collaborative and technologically advanced effort, the CLARUM project promises to shed unprecedented light on the lymphatic system’s enigmatic biology and catalyze breakthroughs that will resonate across genetics, developmental biology, and clinical therapy. The convergence of next-generation sequencing, bioinformatics, and innovative model systems positions this initiative at the forefront of genetic medicine, offering hope to thousands of patients and families affected by these debilitating disorders.
Subject of Research: Genetic basis of congenital lymphatic anomalies and development of advanced diagnostic testing
Article Title: Columbia-Led Consortium Secures $8.7 Million to Advance Genetic Diagnostics for Congenital Lymphatic Diseases
News Publication Date: Not specified
Web References: https://arpa-h.gov/explore-funding/programs/light
Image Credits: Carrie Shawber, Columbia University Irving Medical Center
Keywords: Genetics, Lymphatic system, Congenital lymphatic anomalies, Genetic diagnostics, ARPA-H LIGHT program, Precision medicine, Gene discovery
