Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis

John A. Martignetti, Lifeng Tian, Dong Li, Maria Celeste M. Ramirez, Olga Camacho-Vanegas, Sandra Catalina Camacho, Yiran Guo, Dina J. Zand, Audrey M. Bernstein, Sandra K. Masur, Cecilia E. Kim, Frederick G. Otieno, Cuiping Hou, Nada Abdel-Magid, Ben Tweddale, Denise Metry, Jean Christophe Fournet, Eniko Papp, Elizabeth W. McPherson, Carrie ZabelGuy Vaksmann, Cyril Morisot, Brendan Keating, Patrick M. Sleiman, Jeffrey A. Cleveland, David B. Everman, Elaine Zackai, Hakon Hakonarson

Research output: Contribution to journalArticlepeer-review

145 Scopus citations


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.

Original languageEnglish
Pages (from-to)1001-1007
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number6
StatePublished - 6 Jun 2013


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