Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.

Authors:
John A Martignetti
John A Martignetti
Icahn School of Medicine at Mount Sinai
New York | United States
Lifeng Tian
Lifeng Tian
Thomas Jefferson University
United States
Dong Li
Dong Li
Center for Applied Genomics
Philadelphia | United States
Maria Celeste M Ramirez
Maria Celeste M Ramirez
MedStar Union Memorial Hospital
Baltimore | United States
Olga Camacho-Vanegas
Olga Camacho-Vanegas
Mount Sinai School of Medicine
United States
Sandra Catalina Camacho
Sandra Catalina Camacho
Mount Sinai School of Medicine
United States
Yiran Guo
Yiran Guo
Center for Applied Genomics
Philadelphia | United States
Dina J Zand
Dina J Zand
The Children's Hospital of Philadelphia
United States

Am J Hum Genet 2013 Jun 23;92(6):1001-7. Epub 2013 May 23.

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:

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.

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http://dx.doi.org/10.1016/j.ajhg.2013.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675260PMC
June 2013
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