title: Genetic Variants Associated with Port-Wine Stains.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  Understanding PWS genetic determinants could provide insight into new treatments.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Carolyn and Peter Lynch Center for Laser and Reconstructive Surgery, Division of Facial Plastic and Reconstructive Surgery, Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Alice
authors.initials: A
authors.lastname: Frigerio
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States of America.
authors.forename: Karol
authors.initials: K
authors.lastname: Wright
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States of America; Department of Pathology, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Whitney
authors.initials: W
authors.lastname: Wooderchak-Donahue
authors.affiliation: Carolyn and Peter Lynch Center for Laser and Reconstructive Surgery, Division of Facial Plastic and Reconstructive Surgery, Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Oon T
authors.initials: OT
authors.lastname: Tan
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Margraf
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Stevenson
authors.affiliation: Division of Otolaryngology, Department of Surgery, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: J Fredrik
authors.initials: JF
authors.lastname: Grimmer
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, United States of America; Department of Pathology, University of Utah, Salt Lake City, UT, United States of America.
authors.forename: Pinar
authors.initials: P
authors.lastname: Bayrak-Toydemir
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019339:Port-Wine Stain / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D012867:Skin / Q000378:metabolism / Q000473:pathology; D055815:Young Adult; D020729:p120 GTPase Activating Protein / Q000235:genetics*
chemical_list: C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; C557248:RASA1 protein, human; D020729:p120 GTPase Activating Protein; D043802:GTP-Binding Protein alpha Subunits, Gq-G11