title: Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA.
abstract: OBJECTIVE
  To test the hypothesis that somatic phosphatidylinositol-4,5-bisphospate 3-kinase, catalytic subunit alpha (PIK3CA) mutations would be found in patients with more common disorders including isolated lymphatic malformation (LM) and Klippel-Trenaunay syndrome (KTS).
  
  
  METHODS
  We used next generation sequencing, droplet digital polymerase chain reaction, and single molecule molecular inversion probes to search for somatic PIK3CA mutations in affected tissue from patients seen at Boston Children's Hospital who had an isolated LM (n = 17), KTS (n = 21), fibro-adipose vascular anomaly (n = 8), or congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (n = 33), the disorder for which we first identified somatic PIK3CA mutations. We also screened 5 of the more common PIK3CA mutations in a second cohort of patients with LM (n = 31) from Seattle Children's Hospital.
  
  
  RESULTS
  Most individuals from Boston Children's Hospital who had isolated LM (16/17) or LM as part of a syndrome, such as KTS (19/21), fibro-adipose vascular anomaly (5/8), and congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies syndrome (31/33) were somatic mosaic for PIK3CA mutations, with 5 specific PIK3CA mutations accounting for ∼ 80% of cases. Seventy-four percent of patients with LM from Seattle Children's Hospital also were somatic mosaic for 1 of 5 specific PIK3CA mutations. Many affected tissue specimens from both cohorts contained fewer than 10% mutant cells.
  
  
  CONCLUSIONS
  Somatic PIK3CA mutations are the most common cause of isolated LMs and disorders in which LM is a component feature. Five PIK3CA mutations account for most cases. The search for causal mutations requires sampling of affected tissues and techniques that are capable of detecting low-level somatic mosaicism because the abundance of mutant cells in a malformed tissue can be low.
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Valerie L
authors: VL
authors: Luks
authors: Department of Genetics, Harvard Medical School, Boston, MA.
authors: Nolan
authors: N
authors: Kamitaki
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Matthew P
authors: MP
authors: Vivero
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Wibke
authors: W
authors: Uller
authors: Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA.
authors: Rashed
authors: R
authors: Rab
authors: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Judith V M G
authors: JV
authors: Bovée
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Kristy L
authors: KL
authors: Rialon
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Carlos J
authors: CJ
authors: Guevara
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Ahmad I
authors: AI
authors: Alomari
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Arin K
authors: AK
authors: Greene
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Steven J
authors: SJ
authors: Fishman
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Harry P W
authors: HP
authors: Kozakewich
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Reid A
authors: RA
authors: Maclellan
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: John B
authors: JB
authors: Mulliken
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Reza
authors: R
authors: Rahbar
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Samantha A
authors: SA
authors: Spencer
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Cameron C
authors: CC
authors: Trenor
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Joseph
authors: J
authors: Upton
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: David
authors: D
authors: Zurakowski
authors: Departments of Pediatrics and Surgery, University of Washington, Seattle, WA.
authors: Jonathan A
authors: JA
authors: Perkins
authors: Departments of Pediatrics and Surgery, University of Washington, Seattle, WA.
authors: Andrew
authors: A
authors: Kirsh
authors: Departments of Pediatrics and Surgery, University of Washington, Seattle, WA.
authors: James T
authors: JT
authors: Bennett
authors: Departments of Pediatrics and Surgery, University of Washington, Seattle, WA.
authors: William B
authors: WB
authors: Dobyns
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA.
authors: Kyle C
authors: KC
authors: Kurek
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA; Department of Genetics, Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA. Electronic address: matthew.warman@childrens.harvard.edu.
authors: Matthew L
authors: ML
authors: Warman
authors: Department of Genetics, Harvard Medical School, Boston, MA.
authors: Steven A
authors: SA
authors: McCarroll
authors: Vascular Anomalies Center, Boston Children's Hospital, Boston, MA. Electronic address: rudy.murillo@childrens.harvard.edu.
authors: Rudy
authors: R
authors: Murillo
mesh_terms: D000015:Abnormalities, Multiple; D002648:Child; D002675:Child, Preschool; D058534:Class I Phosphatidylinositol 3-Kinases; D004247:DNA / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007715:Klippel-Trenaunay-Weber Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D044148:Lymphatic Abnormalities / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D054079:Vascular Malformations / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
chemical_list: D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human