Allelic heterogeneity of Proteus syndrome

Cold Spring Harb Mol Case Stud. 2020 Jun 12;6(3):a005181. doi: 10.1101/mcs.a005181. Print 2020 Jun.


Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant in AKT1, a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7.5 yr of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p.(Glu17Arg) variant in AKT1 at a variant allele fraction that ranged from <0.01 to 0.46 in fibroblasts established from an overgrown digit. This variant was demonstrated to be constitutively activating by phosphorylation of AKT(S473). These data document allelic heterogeneity for Proteus syndrome. We recommend that individuals with a potential clinical diagnosis of Proteus syndrome who are negative for the p.(Glu17Lys) variant be tested for other variants in AKT1.

Keywords: contractures of the large joints; fibrocystic lung disease; increased adipose tissue; lower limb asymmetry; overgrowth; upper limb asymmetry; venous malformation.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Alleles*
  • Allelic Imbalance
  • Amino Acid Substitution
  • Cervical Vertebrae / abnormalities
  • Cervical Vertebrae / diagnostic imaging
  • Genetic Association Studies
  • Genetic Heterogeneity*
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Medical History Taking
  • Mutation*
  • Phenotype
  • Proteus Syndrome / diagnosis*
  • Proteus Syndrome / genetics*
  • Proto-Oncogene Proteins c-akt / genetics*
  • Radiography
  • Symptom Assessment


  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt