title: A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth.
abstract: BACKGROUND
  Capillary malformation is a cutaneous vascular anomaly that is present at birth, darkens over time, and can cause overgrowth of tissues beneath the stain. The lesion is caused by a somatic activating mutation in GNAQ. In a previous study, we were unable to identify a GNAQ mutation in patients with a capillary malformation involving an overgrown lower extremity. We hypothesized that mutations in GNA11 or GNA14, genes closely related to GNAQ, also may cause capillary malformations.
  
  
  METHODS
  Human capillary malformation tissue obtained from 8 patients that had tested negative for GNAQ mutations were studied. Lesions involved an extremity (n = 7) or trunk (n = 1). Droplet digital PCR (ddPCR) was used to detect GNA11 or GNA14 mutant cells (p.Arg183) in the specimens. Single molecule molecular inversion probe sequencing (smMIP-seq) was performed to search for other mutations in GNA11. Mutations were validated by subcloning and sequencing amplimers.
  
  
  RESULTS
  We found a somatic GNA11 missense mutation (c.547C > T; p.Arg183Cys) in 3 patients with a diffuse capillary malformation of an extremity. Mutant allelic frequencies ranged from 0.3 to 5.0%. GNA11 or GNA14 mutations were not found in 5 affected tissues or in unaffected tissues (white blood cell DNA).
  
  
  CONCLUSIONS
  GNA11 mutations are associated with extremity capillary malformations causing overgrowth. Pharmacotherapy that affects GNA11 signaling may prevent the progression of capillary malformations.
authors.affiliation: Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Couto
authors.affiliation: Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Ugur M
authors.initials: UM
authors.lastname: Ayturk
authors.affiliation: Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Konczyk
authors.affiliation: Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goss
authors.affiliation: Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: August Y
authors.initials: AY
authors.lastname: Huang
authors.affiliation: Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Hann
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Reeve
authors.affiliation: Department of Dermatology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Liang
authors.affiliation: Department of Surgery, Vascular Biology Program, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.affiliation: Department of Orthopedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Warman
authors.affiliation: Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. arin.greene@childrens.harvard.edu.
authors.forename: Arin K
authors.initials: AK
authors.lastname: Greene
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002196:Capillaries / Q000002:abnormalities*; D002648:Child; D005121:Extremities / Q000473:pathology*; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D054079:Vascular Malformations / Q000235:genetics*; D055815:Young Adult
chemical_list: C554062:GNA11 protein, human; D044385:GTP-Binding Protein alpha Subunits
keywords: Capillary malformation; Extremity; GNA11; GNAQ; Vascular anomaly