Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 92, Issue 6, Pages 996-1000Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.04.026
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Funding
- Canadian Gene Cure Foundation
- Fonds de la Recherche en sante au Quebec (FRSQ)
- National Institutes of Health [PO1 HD22657, PO1 HD070394]
- Rolanette and Berdon Lawrence Bone Disease Program of Texas
- NIH [U54 HG006542, U54 HG003273]
- Ruth L. Kirschstein National Research Service [F30 MH098571-01]
- CIHR
- Government of Canada through Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute [OGI-049]
- Genome Quebec
- Genome British Columbia
- McLaughlin Centre
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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 beta (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-beta promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in W. Our findings indicate p.Arg561Cys substitution in PDGFR:13 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-beta in aggressive life-threatening familial forms of the disease.
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