title: Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.
abstract: Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA; Department of Pediatrics, Mount Sinai School of Medicine, New York, NY 10029, USA; Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA. Electronic address: john.martignetti@mssm.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
authors.forename: Lifeng
authors.initials: L
authors.lastname: Tian
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Maria Celeste M
authors.initials: MC
authors.lastname: Ramirez
authors.forename: Olga
authors.initials: O
authors.lastname: Camacho-Vanegas
authors.forename: Sandra Catalina
authors.initials: SC
authors.lastname: Camacho
authors.forename: Yiran
authors.initials: Y
authors.lastname: Guo
authors.forename: Dina J
authors.initials: DJ
authors.lastname: Zand
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Bernstein
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Masur
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Otieno
authors.forename: Cuiping
authors.initials: C
authors.lastname: Hou
authors.forename: Nada
authors.initials: N
authors.lastname: Abdel-Magid
authors.forename: Ben
authors.initials: B
authors.lastname: Tweddale
authors.forename: Denise
authors.initials: D
authors.lastname: Metry
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Fournet
authors.forename: Eniko
authors.initials: E
authors.lastname: Papp
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: McPherson
authors.forename: Carrie
authors.initials: C
authors.lastname: Zabel
authors.forename: Guy
authors.initials: G
authors.lastname: Vaksmann
authors.forename: Cyril
authors.initials: C
authors.lastname: Morisot
authors.forename: Brendan
authors.initials: B
authors.lastname: Keating
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sleiman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Cleveland
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.forename: Elaine
authors.initials: E
authors.lastname: Zackai
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D018224:Myofibromatosis / Q000151:congenital* / Q000235:genetics; D010375:Pedigree; D000071656:Receptor, Notch3; D020797:Receptor, Platelet-Derived Growth Factor beta / 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