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

Andrew M. Piacitelli, Dana M. Jensen, Heather Brandling-Bennett, Megan Mariner Gray, Maneesh Batra, Juliane Gust, Ameet Thaker, Catherine Paschal, Karen Tsuchiya, Colin C. Pritchard, Jonathan Perkins, Ghayda M. Mirzaa, James T. Bennett

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2301-2308
Number of pages8
JournalAmerican Journal of Medical Genetics, Part A
Volume176
Issue number11
DOIs
StatePublished - Nov 2018

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Keywords

  • PIK3CA
  • ddPCR
  • mosaicism
  • overgrowth
  • vascular malformation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Piacitelli, A. M., Jensen, D. M., Brandling-Bennett, H., Gray, M. M., Batra, M., Gust, J., Thaker, A., Paschal, C., Tsuchiya, K., Pritchard, C. C., Perkins, J., Mirzaa, G. M., & Bennett, J. T. (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. American Journal of Medical Genetics, Part A, 176(11), 2301-2308. https://doi.org/10.1002/ajmg.a.40487