Sturge–Weber Syndrome and Port-Wine Stains Caused by Somatic Mutation inGNAQ

Abstract

BACKGROUND The Sturge–Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability. It has been hypothesized that somatic mosaic mutations disrupting vascular development cause both the Sturge–Weber syndrome and port-wine stains, and the severity and extent of presentation are determined by the developmental time point at which the mutations occurred. To date, no such mutation has been identified. METHODS We performed whole-genome sequencing of DNA from paired samples of visibly affected and normal tissue from 3 persons with the Sturge–Weber syndrome. We tested for the presence of a somatic mosaic mutation in 97 samples from 50 persons with the Sturge–Weber syndrome, a port-wine stain, or neither (controls), using amplicon sequencing and SNaPshot assays, and investigated the effects of the mutation on downstream signaling, using phosphorylation-specific antibodies for relevant effectors and a luciferase reporter assay. RESULTS We identified a nonsynonymous single-nucleotide variant (c.548G→A, p.Arg183Gln) in GNAQ in samples of affected tissue from 88% of the participants (23 of 26) with the Sturge–Weber syndrome and from 92% of the participants (12 of 13) with apparently nonsyndromic port-wine stains, but not in any of the samples of affected tissue from 4 participants with an unrelated cerebrovascular malformation or in any of the samples from the 6 controls. The prevalence of the mutant allele in affected tissues ranged from 1.0 to 18.1%. Extracellular signal-regulated kinase activity was modestly increased during transgenic expression of mutant Gαq. CONCLUSIONS The Sturge–Weber syndrome and port-wine stains are caused by a somatic activating mutation in GNAQ. This finding confirms a long-standing hypothesis. (Funded by the National Institutes of Health and Hunter’s Dream for a Cure Foundation.)

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

“…For analysis of mutant allele frequencies in the exome database, we adopted standard practices and controls used by a similar study. 28 A total of 2,508 aligned CRAM (compressed BAM) files were downloaded from the 1000 Genomes Project FTP (alignment released May 2, 2013). For all 2,508 alignments, we evaluated three genomic positions (chr9: 135,797,259 for TSC1 c.610C>T; chr9: 135,804,196 for TSC1 c.64C>T; and chr16: 2,135,300 for TSC2 c.4639 C>T) to find supporting mutations in normal individuals.…”

Whole-Exome Sequencing and Whole-Genome Sequencing in Critically Ill Neonates Suspected to Have Single-Gene Disorders

“…In addition to germline mutations, somatic or post-zygotic mutations also occur, causing genetic diseases. In the context of neo-natal medicine, this would be most important for disorders related to mosaicism such as in McCune -Albright syndrome, incontinentia pigmenti, and Sturge -Weber syndrome (van den Akker et al 2009;Erickson 2010;Shirley et al 2013). Mosaicism is probably more common than previously thought, with parental germline mosaicism in singleton children with genetic diseases estimated to be at least 4% (Huisman et al 2013;Campbell et al 2014).…”

Sturge Weber Syndrome: review of literature with case illustration

“…[14] Treatment revolves primarily around seizure control, with surgical resection only indicated rarely in refractory cases. Ophthalmological examination is also essential to identify and treat ocular involvement [18,19] …”