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A breakthrough study conducted by researchers at Children’s Hospital of Philadelphia (CHOP) has revealed that comprehensive "deep sequencing" of the genome in tissue samples and cell-free DNA of patients with vascular anomalies uncovers previously undetected genetic variants related to the disease. The identification of these variants led to targeted therapies and resulted in significant improvements in over 60% of patients' conditions. The findings, published in Nature Medicine, offer hope for better understanding and treating life-threatening vascular anomalies.
Vascular anomalies encompass a range of conditions affecting veins, arteries, and the lymphatic system, classified as vascular tumors or vascular malformations. While some anomalies resolve naturally, others cause visible deformities, hinder organ functions, or inflict severe pain, with certain cases posing life-threatening risks.
Building on a previous study where CHOP researchers identified a genetic variant responsible for a lymphatic system anomaly, the team sought to explore the potential of targeted therapies for other patients with vascular anomalies. Conventional genetic testing methods often failed to capture the gene variants driving these conditions due to limited access to affected tissue samples or insufficient genomic sequencing information.
Lead author Dr. Hakon Hakonarson explained, "The disease-causing variant in the mutated gene of interest is present in frequencies of less than 1 percent, which makes them hard to detect with conventional sequencing approaches." To overcome this limitation, the researchers performed deep sequencing on DNA samples from 356 patients, specifically analyzing CD31+ cells and cell-free DNA isolated from lymphatic fluid or plasma.
Deep sequencing, involving repeated sequencing of specific genomic regions, enabled the detection of somatic variants with an allele frequency as low as 0.15% in a given specimen. This approach led to the identification of previously unknown genetic causes in 41% of patients with primary complex lymphatic anomalies and 72% of patients with vascular malformations. As a result, 69 patients received or planned to receive new targeted therapies, and a significant 63% experienced marked improvement in their symptoms.
The ability to link the patient's specific symptoms to the underlying genetic variant has been transformative for patients, as explained by Dr. Denise Adams, Director of the Comprehensive Vascular Anomalies Program at CHOP. The findings not only provided a molecular diagnosis but also enabled the administration of directed medical therapies, greatly improving patients' quality of life.
The study's co-leader, Dr. Sarah Sheppard, highlighted the interdisciplinary approach, combining molecular studies with functional investigations in organoids and zebrafish, which ultimately guided medical therapy decisions. The comprehensive findings lay the foundation for future applications of cell-free DNA (cfDNA) technology as a non-invasive molecular diagnostic tool for all patients with vascular anomalies.
The Comprehensive Vascular Anomalies Program (CVAP) at CHOP, a Frontier Program, played a crucial role in the study. Through state-of-the-art genomics and personalized research strategies, CVAP strives to understand complex vascular conditions and identify targeted therapies. The program, comprising specialists from various disciplines, provides comprehensive care for pediatric patients with rare, life-threatening vascular tumors and malformations. By leveraging clinical and genomic research capacities, CHOP aims to transform the understanding and treatment of these life-threatening conditions.
Vascular anomalies encompass a range of conditions affecting veins, arteries, and the lymphatic system, classified as vascular tumors or vascular malformations. While some anomalies resolve naturally, others cause visible deformities, hinder organ functions, or inflict severe pain, with certain cases posing life-threatening risks.
Building on a previous study where CHOP researchers identified a genetic variant responsible for a lymphatic system anomaly, the team sought to explore the potential of targeted therapies for other patients with vascular anomalies. Conventional genetic testing methods often failed to capture the gene variants driving these conditions due to limited access to affected tissue samples or insufficient genomic sequencing information.
Lead author Dr. Hakon Hakonarson explained, "The disease-causing variant in the mutated gene of interest is present in frequencies of less than 1 percent, which makes them hard to detect with conventional sequencing approaches." To overcome this limitation, the researchers performed deep sequencing on DNA samples from 356 patients, specifically analyzing CD31+ cells and cell-free DNA isolated from lymphatic fluid or plasma.
Deep sequencing, involving repeated sequencing of specific genomic regions, enabled the detection of somatic variants with an allele frequency as low as 0.15% in a given specimen. This approach led to the identification of previously unknown genetic causes in 41% of patients with primary complex lymphatic anomalies and 72% of patients with vascular malformations. As a result, 69 patients received or planned to receive new targeted therapies, and a significant 63% experienced marked improvement in their symptoms.
The ability to link the patient's specific symptoms to the underlying genetic variant has been transformative for patients, as explained by Dr. Denise Adams, Director of the Comprehensive Vascular Anomalies Program at CHOP. The findings not only provided a molecular diagnosis but also enabled the administration of directed medical therapies, greatly improving patients' quality of life.
The study's co-leader, Dr. Sarah Sheppard, highlighted the interdisciplinary approach, combining molecular studies with functional investigations in organoids and zebrafish, which ultimately guided medical therapy decisions. The comprehensive findings lay the foundation for future applications of cell-free DNA (cfDNA) technology as a non-invasive molecular diagnostic tool for all patients with vascular anomalies.
The Comprehensive Vascular Anomalies Program (CVAP) at CHOP, a Frontier Program, played a crucial role in the study. Through state-of-the-art genomics and personalized research strategies, CVAP strives to understand complex vascular conditions and identify targeted therapies. The program, comprising specialists from various disciplines, provides comprehensive care for pediatric patients with rare, life-threatening vascular tumors and malformations. By leveraging clinical and genomic research capacities, CHOP aims to transform the understanding and treatment of these life-threatening conditions.