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.

Figure 1

Pedigrees of Nine Unrelated IM Families The inheritance pattern in all the families used in this study was consistent with autosomal-dominant transmission. Five families have been previously reported: IM-1, IM-2, IM-6, IM-7, IM-8. Asterisk indicates that these samples were whole-exome sequenced.

Figure 2

Mutations in PDGFRB and NOTCH3 (A) Representative sequence chromatograms for each of the different mutations identified. (B) Conservation of the mutations and the surrounding region in vertebrates. Arrows indicate the positions of the mutated alleles.

Figure 3

Tumor Cell Lines Derived from Affected Individuals Demonstrate a Myofibroblastic Phenotype Vimentin (green) and a-SMA (red) staining of tumor cell lines from members of family IM-9. Cells were cultured from a soft-tissue tumor excised from an affected area on the affected individual’s back as part of their care. Three paired views at 20× (left column) and 40× (right column) are shown.