Shirley et al. (2013) performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 patients with Sturge-Weber syndrome (SWS; 185300) and identified 1 nonsynonymous somatic single-nucleotide variant, a c.548G-A transition in the GNAQ gene, resulting in an arg183-to-gln (R183Q) substitution at a highly conserved residue, that was present in all 3 affected samples and was not present in the normal-appearing samples. Screening of additional SWS patients as well as individuals with nonsyndromic port-wine stains (163000) revealed that all 9 SWS patients were positive for the R183Q mutation in port-wine-stained skin, 6 (86%) of 7 participants with SWS were negative for the mutation in visibly normal skin, and 12 (92%) of 13 participants with nonsyndromic port-wine stains were positive for the mutation. The mutation was also detected in brain samples from 15 (83%) of 18 SWS patients, whereas all 6 brain samples from normal controls were negative. Transfection studies in HEK 293T cells showed significant activation of ERK (600997) by the R183Q mutant compared to control. Overall, 23 (88%) of 26 SWS patients were positive for the gain-of-function R183Q mutation in either port wine-stained skin or brain tissue. Shirley et al. (2013) suggested that nonsyndromic port-wine stains may represent a late origin of the somatic GNAQ mutation in vascular endothelial cells, whereas in Sturge-Weber syndrome, the mutation may occur earlier in development, in progenitor cells that are precursors to a larger variety of cell types and tissues, leading to the syndromic phenotype. Five (0.7%) of 669 samples from the 1000 Genomes Project database were positive for R183Q; noting that the reported prevalence of port-wine stains is 0.3% to 0.5%, Shirley et al. (2013) hypothesized that the 0.7% prevalence in that database represented the occurrence of port-wine stains in the population.
In tissue from a patient with a sporadic long-standing unilateral facial port-wine stain, Lian et al. (2014) detected the GNAQ R183Q mutation at an allelic fraction of 0.05 in PWS tissue; the mutation was not found in paired normal tissue. The percentage of GNAQ mutation was consistent with the percentage of lesional endothelial cells in the specimen.
