Defective morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations, a relatively common congenital malformation. Current therapies are primarily invasive and can produce significant morbidity. Most vascular malformations are due to post-zygotic (mosaic) activating mutations in a few oncogenes (PIK3CA, KRAS, MAP2K1, others) in the PI3K-AKT and RAS-MAPK pathways. These mutations are never present in DNA derived from white blood cells, the most common sample for genetic testing, making molecular diagnosis challenging. Long-term, our goal is to improve treatment of individuals with vascular malformations. The proposed experiments advance that goal by expanding diagnostic options for VM patients and dissecting cellular and spatial heterogeneity in vascular malformations, using novel, cutting edge technologies.
Our first aim i s to determine if non-invasive ?liquid biopsies? of plasma derived cell-free DNA can detect mosaic mutations in individuals with vascular malformations. Since mutations driving vascular malformations are typically present only in the malformation itself, an invasive surgery or biopsy is currently required for diagnosis. Since a molecular diagnosis is required to guide targeted drug therapies (such as PI3K or AKT inhibitors, for which clinical trials are currently open), developing non-invasive diagnostics for vascular malformations would have immediate patient impact. Next, we will study how gene expression changes in single cells in vascular malformation tissues and integrate this information with each cell's mutation status, using a novel, multi-omics method. We will also use techniques that allow us to visualize how gene expression changes in two and three dimensional space within vascular malformations. Since only a small fraction (1-10%) of cells inside vascular malformations typically possess the driving mutation, these experiments will help us understand how small cell populations can produce large, multicellular malformations. We have assembled a multidisciplinary team with non-overlapping areas of expertise to accomplish these goals. Our experiments will be performed using samples from a large, pre-existing biorepository of vascular malformation samples rich in clinical data. We expect this work to expand our understanding of vascular malformations and vascular biology specifically, and the nature of mosaicism more generally.
Vascular malformations occur when there is abnormal development of the body's blood or lymphatic vessels. They are a relatively common birth defect and can produce significant health issues in children and adults. By developing new diagnostic methods and trying to understand how these malformations form in the first place, we will expand available treatment options and improve the lives of individuals with vascular malformations.
|Steiner, Jack E; McCoy, Garrett N; Hess, Christopher P et al. (2018) Structural malformations of the brain, eye, and pituitary gland in PHACE syndrome. Am J Med Genet A 176:48-55|
|Li, Dong; Wenger, Tara L; Seiler, Christoph et al. (2018) Pathogenic variant in EPHB4 results in central conducting lymphatic anomaly. Hum Mol Genet 27:3233-3245|
|Ramos, Eliana Marisa; Carecchio, Miryam; Lemos, Roberta et al. (2018) Primary brain calcification: an international study reporting novel variants and associated phenotypes. Eur J Hum Genet 26:1462-1477|
|Piacitelli, Andrew M; Jensen, Dana M; Brandling-Bennett, Heather et al. (2018) Characterization of a severe case of PIK3CA-related overgrowth at autopsy by droplet digital polymerase chain reaction and report of PIK3CA sequencing in 22 patients. Am J Med Genet A 176:2301-2308|
|Padia, Reema; Bly, Randall; Bull, Catherine et al. (2018) Medical Management of Vascular Anomalies. Curr Treat Options Pediatr 4:221-236|
|Bly, Randall A; Perkins, Jonathan; Parikh, Sanjay R (2017) Can topical beta-blockers reduce the size of superficial infantile hemangiomas of the head and neck? Laryngoscope 127:4-5|
|Bennett, James T; Tan, Tiong Yang; Alcantara, Diana et al. (2016) Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. Am J Hum Genet 98:579-587|
|Mirzaa, Ghayda; Timms, Andrew E; Conti, Valerio et al. (2016) PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight 1:|
|Strub, Graham M; Kirsh, Andrew L; Whipple, Mark E et al. (2016) Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma. JCI Insight 1:e88856|
|Luks, Valerie L; Kamitaki, Nolan; Vivero, Matthew P et al. (2015) Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr 166:1048-54.e1-5|