title: A recurrent PDGFRB mutation causes familial infantile myofibromatosis.
abstract: Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.
authors.affiliation: Department of Pediatrics, Columbia University, New York, NY 10032, USA.
authors.forename: Yee Him
authors.initials: YH
authors.lastname: Cheung
authors.forename: Tenzin
authors.initials: T
authors.lastname: Gayden
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: Donna
authors.initials: D
authors.lastname: Russo
authors.forename: Van-Hung
authors.initials: VH
authors.lastname: Nguyen
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Guo
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Guan
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.forename: Brenda
authors.initials: B
authors.lastname: Moroz
authors.forename: Karen W
authors.initials: KW
authors.lastname: Eldin
authors.forename: James T
authors.initials: JT
authors.lastname: Lu
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: David
authors.initials: D
authors.lastname: Malkin
authors.forename: Albert M
authors.initials: AM
authors.lastname: Berghuis
authors.forename: Sherif
authors.initials: S
authors.lastname: Emil
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: David L
authors.initials: DL
authors.lastname: Burk
authors.forename: Megan
authors.initials: M
authors.lastname: Vanstone
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Orchard
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
mesh_terms: D000595:Amino Acid Sequence; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D018224:Myofibromatosis / Q000151:congenital* / Q000235:genetics; D010375:Pedigree; D017434:Protein Structure, Tertiary; D000071656:Receptor, Notch3; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D020797:Receptor, Platelet-Derived Growth Factor beta