Genetic Variants Associated with Port-Wine Stains

• Published in: PloS one 2015-07, Vol.10 (7), p.e0133158-e0133158
• Main Authors: Frigerio, Alice, Wright, Karol, Wooderchak-Donahue, Whitney, Tan, Oon T, Margraf, Rebecca, Stevenson, David A, Grimmer, J Fredrik, Bayrak-Toydemir, Pinar
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Alleles; Background noise; Biopsy; Comparative analysis; Deoxyribonucleic acid; Dermis; DNA; Female; Gene frequency; Gene sequencing; Genes; Genetic diversity; Genetic variance; Genetic Variation; Genomes; Genomics; Glutamine; GTP-Binding Protein alpha Subunits - genetics; GTP-Binding Protein alpha Subunits, Gq-G11; Head and neck; High-Throughput Nucleotide Sequencing; Humans; Lasers; Low level; Male; Middle Aged; Mosaicism; Mutation; Otology; p120 GTPase Activating Protein - genetics; Pathology; Polymerase chain reaction; Polymorphism, Genetic; Port-Wine Stain - genetics; Port-Wine Stain - pathology; Sequence Analysis, DNA; Skin; Skin - metabolism; Skin - pathology; Stains; Stains & staining; Studies; Wine; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0133158

Port-wine stains (PWS) are capillary malformations, typically located in the dermis of the head and neck, affecting 0.3% of the population. Current theories suggest that port-wine stains are caused by somatic mutations that disrupt vascular development. Understanding PWS genetic determinants could provide insight into new treatments. Our study used a custom next generation sequencing (NGS) panel and digital polymerase chain reaction to investigate genetic variants in 12 individuals with isolated port-wine stains. Importantly, affected and healthy skin tissue from the same individual were compared. A subtractive correction method was developed to eliminate background noise from NGS data. This allowed the detection of a very low level of mosaicism. A novel somatic variant GNAQ, c.547C>G, p.Arg183Gly was found in one case with 4% allele frequency. The previously reported GNAQ c.548G>A, p.Arg183Gln was confirmed in 9 of 12 cases with an allele frequency ranging from 1.73 to 7.42%. Digital polymerase chain reaction confirmed novel variants detected by next generation sequencing. Two novel somatic variants were also found in RASA1, although neither was predicted to be deleterious. This is the second largest study on isolated, non-syndromic PWS. Our data suggest that GNAQ is the main genetic determinant in this condition. Moreover, isolated port-wine stains are distinct from capillary malformations seen in RASA1 disorders, which will be helpful in clinical evaluation.