Recent experience suggests that post-zygotic or mosaic mutations are a common cause of developmental disorders that can involve any organ system, although they are most easily recognized in vascular anomalies and skin. Several genes underlying rare syndromes with vascular anomalies have been identified, but so far only two that contribute to the more common non-syndromic forms: TEK for venous malformations and PIK3CA for lymphatic malformations, the latter recent work reported by the investigators. For both of these and several syndromic forms, the mutations are found in only or primarily in affected tissue and represent mosaic mutations. We propose to identify and study the genes underlying other vascular anomalies using new genomics technologies. The genetics community has rapidly moved to whole exome (WXS) or whole genome (WGS) sequencing to investigate disorders such as these, but the success rate of such studies is only ~25% when germline inheritance is expected, and much lower for patchy or asymmetric disorders that suggest mosaicism.
Our first aim i s to develop new genomic and bioinformatics methods that will more reliably detect low level mosaic mutations using massively parallel (NextGen) sequencing approaches. We will next study how the level and distribution of mosaicism affects the phenotype, focusing first on disorders with known causative genes (initially PIK3CA) that can be evaluated reliably because of vascular and/or lymphatic involvement. Finally, we will use existing and new methods to search for novel genes underlying vascular anomalies, focusing first on more common and clinically important types such as such as arteriovenous malformations, the remaining unexplained lymphatic malformations (that is, not due to PIK3CA mutations) and hemangiomas. We expect this work to significantly expand our understanding of vascular anomalies specifically and the nature of mosaicism more broadly.

Public Health Relevance

Many genetic disorders affect every cell in the body, but an emerging class of disorders is caused by 'mosaic' changes or genetic mutations that affect only a portion of cells in the body. The patchy nature of most vascular anomalies suggests that they are caused by mosaic mutations of the underlying genes. We propose to develop new methods to find these 'mosaic' genetic changes, and apply them to developmental disorders of blood and lymphatic vessels that present with asymmetric or patchy features of disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Tolunay, Eser
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Seattle Children's Hospital
United States
Zip Code
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