@article{e292081ff2e940aba372137e813e86f1,
title = "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",
abstract = "PIK3CA-related overgrowth spectrum (PROS) refers to a group of disorders of segmental overgrowth of a wide variety of tissues as well as venous and lymphatic malformations. Clinical and molecular diagnosis can be challenging due to phenotypic heterogeneity and difficulties detecting low-level mosaicism using standard methods. Here, we report a patient with a severe presentation of PIK3CA-related overgrowth with analysis of 27 posthumously collected tissues by droplet digital polymerase chain reaction (PCR) at autopsy. This patient had a complicated medical course, with coagulopathy, ischemic brain injury, and sepsis resulting in multi-organ failure and death at age 2 months despite sirolimus therapy. Five of the 27 tissues analyzed possessed a mosaic PIK3CA mutation (p.E545K), with mutation levels ranging from 3 to 20% across affected tissues. We found no correlation between tissue-specific disease severity and mutation levels, likely reflecting sampling limitations. We also tested a series of 22 individuals with somatic overgrowth and/or vascular-lymphatic malformations using a targeted next generation sequencing panel and found PIK3CA mutations in nine individuals, identifying three novel PIK3CA variants. This report expands the clinical and molecular spectrum of PROS, emphasizes that different molecular methods can be complimentary in the diagnosis of these disorders, and highlights the risk of coagulopathy in a subset of patients with PIK3CA-related overgrowth.",
keywords = "PIK3CA, ddPCR, mosaicism, overgrowth, vascular malformation",
author = "Piacitelli, {Andrew M.} and Jensen, {Dana M.} and Heather Brandling-Bennett and Gray, {Megan Mariner} and Maneesh Batra and Juliane Gust and Ameet Thaker and Catherine Paschal and Karen Tsuchiya and Pritchard, {Colin C.} and Jonathan Perkins and Mirzaa, {Ghayda M.} and Bennett, {James T.}",
note = "Funding Information: The authors sincerely thank the family of patient LR16-397 for their support of our research. This study was funded by the Seattle Children{\textquoteright}s Hospital Guild Funding Focus Award, NIH RO1 NS092772, and NIGMS-ID 905693 (JP); the National Institutes of Neurological Disorders and Stroke (NINDS) grant K08NS092898 and Jordan{\textquoteright}s Guardian Angels (GM); and the Burroughs Wellcome Fund Career Award 1014700 for Medical Scientists (JTB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication. Also, the authors would like to thank Dr. Brian Gordon from the Seattle Children{\textquoteright}s Research Institute for providing technical expertise regarding ddPCR and Dr. Murat Maga for assistance with generating Figure 2. Funding Information: The authors sincerely thank the family of patient LR16-397 for their support of our research. This study was funded by the Seattle Children's Hospital Guild Funding Focus Award, NIH RO1 NS092772, and NIGMS-ID 905693 (JP); the National Institutes of Neurological Disorders and Stroke (NINDS) grant K08NS092898 and Jordan's Guardian Angels (GM); and the Burroughs Wellcome Fund Career Award 1014700 for Medical Scientists (JTB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication. Also, the authors would like to thank Dr. Brian Gordon from the Seattle Children's Research Institute for providing technical expertise regarding ddPCR and Dr. Murat Maga for assistance with generating Figure. Funding Information: Burroughs Wellcome Fund, Grant/Award Numbers: 1014700 , Award 1014700; National Institute of Neurological Disorders and Stroke, Grant/Award Number: K08NS092898 NS092772; National Institutes of Neurological Disorders and Stroke (NINDS), Grant/Award Number: K08NS092898; Seattle Children{\textquoteright}s Hospital, Grant/Award Number: NIH RO1 NS092772, and NIGMS-ID 905693 Publisher Copyright: {\textcopyright} 2018 Wiley Periodicals, Inc.",
year = "2018",
month = nov,
doi = "10.1002/ajmg.a.40487",
language = "English (US)",
volume = "176",
pages = "2301--2308",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "11",
}