Leslie Biesecker and colleagues report exome sequencing identifying the genetic basis of Proteus syndrome (N. Engl. J. Med., published online 27 July 2011; doi:10.1056/NEJMoa1104017). Proteus syndrome is a rare developmental disorder characterized by severe overgrowths of tissue and bones that is also widely known by the name 'Elephant Man syndrome'. The authors sequenced 12 exomes, including 6 individuals with Proteus syndrome, their parents and one unaffected identical twin. They included samples from both affected and unaffected tissue and followed this with validation sequencing in additional cases, identifying somatic mutations in AKT1 in 26 of 29 of individuals with Proteus syndrome. The AKT1 mutation was found only in affected tissues, providing further support for the genetic mosaicism hypothesis proposed for this disorder over 20 years ago. Using an assay for AKT activation in tissues from cases and controls, the authors found that this AKT1 mutation causes constitutive activation of AKT in affected tissues. AKT1 is in the same regulatory pathways as PTEN, which has previously been associated with Proteus-like syndromes. This may explain some of the clinical overlap in these segmental overgrowth disorders.