Jonathan Pevsner, Douglas Marchuk, Anne Comi and colleagues report whole-genome sequencing of three individuals with Sturge-Weber syndrome, a neurological and skin disease characterized by abnormal blood vessel development, glaucoma, seizures, intellectual disability and port-wine stain of the skin (N. Engl. J. Med. doi:10.1056/NEJMoa1213507, 8 May 2013). They identified a missense mutation, encoding p.Arg183Gln, in the GNAQ gene in affected skin or brain tissue from all three individuals, whereas the mutation was not present in tissue taken from unaffected areas. They looked for the mutation in additional individuals with Sturge-Weber syndrome and in total identified the mutation in affected tissues from 23 of 26 tested individuals. They also identified the same mutation in affected tissues from 12 of 13 tested individuals with nonsyndromic port-wine stain. GNAQ encodes Gαq, a G protein subunit involved in G protein–coupled receptor signaling. The authors further determined that the p.Arg183Gln substitution causes modestly elevated activation of downstream mitogen-activated protein kinase (MAPK) signaling. They hypothesize that early developmental origin of the somatic mutation causes Sturge-Weber syndrome, whereas later origin causes nonsyndromic port-wine stain.