New Information on Sturge-Weber Syndrome Somatic Mutation

DECEMBER 5, 2014

Question: Is there any new information out on the Sturge-Weber syndrome somatic mutation?

Answer: Two studies have been published since our ground-breaking discovery last year. We showed that a genetic change in a gene called GNAQ occurring during fetal development, which is NOT inherited and only affects some cells of the body, causes Sturge-Weber syndrome. Since then, there have been two follow-up studies published based on this finding.

  • The first study confirmed the finding of the same GNAQ mutation in 15 out of the 18 Sturge-Weber syndrome brain tissue samples studied. This genetic change in GNAQ was NOT found in the blood samples of the same subjects with Sturge-Weber syndrome. These results confirm for the first time what we would predict, namely that in order to test for the somatic mutation in GNAQ at tissue sample, either skin or brain, is required. Please see abstract below.

Nakashima M, Miyajima M, Sugano H, Iimura Y, Kato M, Tsurusaki Y, Miyake N, Saitsu H, Arai H, Matsumoto N. (2014). The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome. Journal of Human Genetics. doi: 10.1038/jhg.2014.95.

The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome. Nakashima M, Miyajima M, Sugano H, Iimura Y, Kato M, Tsurusaki Y, Miyake N, Saitsu H, Arai H, Matsumoto N. Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by capillary malformation (port-wine stains), and choroidal and leptomeningeal vascular malformations. Previously, the recurrent somatic mutation c.548G>A (p.R183Q) in the G-α q gene (GNAQ) was identified as causative in SWS and non-syndromic port-wine stain patients using whole-genome sequencing. In this study, we investigated somatic mutations in GNAQ by next-generation sequencing. We first performed targeted amplicon sequencing of 15 blood-brain-paired samples in sporadic SWS and identified the recurrent somatic c.548G>A mutation in 80% of patients (12 of 15). The percentage of mutant alleles in brain tissues of these 12 patients ranged from 3.6 to 8.9%. We found no other somatic mutations in any of the seven GNAQ exons in the remaining three patients without c.548G>A. These findings suggest that the recurrent somatic GNAQ mutation c.548G>A is the major determinant genetic factor for SWS and imply that other mutated candidate gene(s) may exist in SWS.

The second recently published study building upon our discovery is a single case report that is a bit harder to interpret. The reseachers found not only the GNAQ mutation, but also several other mutations in SMARCA4, EPHA3, MYB, PDGFR-β, and PIK3CA., which we did NOT find when we did Whole genome sequencing of our three pairs of normal and port-wine samples from three subjects with Sturge-Weber syndrome. It is possible that these genes in some way contribute to the evolution of port-wine birthmarks. However, somatic mutations are occurring in all of us all the time, therefore further study is needed to determine what if any involvement any of these mutation have. Please see the abstract below:

Lian CG, Sholl LM, Zakka LR, O TM, Liu C, Xu S, Stanek E, Garcia E, Jia Y, MacConaill LE, Murphy GF, Waner M, Mihm MC Jr. (2014). Novel Genetic Mutations in a Sporadic Port-Wine Stain. JAMA Dermatology. doi: 10.1001/jamadermatol.2014.1244.

Port-wine stains (PWSs) are common congenital cutaneous capillary malformations. A somatic GNAQ mutation was recently identified in patients with sporadic PWSs and Sturge-Weber syndrome. However, subsequent studies to confirm or extend this observation are lacking. We report a long-standing, unilateral facial PWS of a man in his early 70s confirmed by histopathological analysis. Staged surgical excision of the vascular malformation was performed, and genomic DNA was extracted from the vascular malformation specimen and normal skin. Targeted next-generation sequencing of the coding sequence of 275 known cancer genes including GNAQ was performed in both specimens. A single-nucleotide variant (c.548G>A, p.Arg183Gln) in GNAQ was identified in the PWS-affected tissue but not in the normal skin sample. In addition, this sequencing approach uncovered several additional novel somatic mutations in the genes SMARCA4, EPHA3, MYB, PDGFR-β, and PIK3CA. Our findings confirm the presence of somatic mutations in GNAQ in the affected skin of a patient with congenital PWS, as well as alterations in several other novel genes of possible importance in the pathogenesis of PWS that may also offer substantial therapeutic targets.

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