Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions

Am J Hum Genet. 2017 Dec 7;101(6):985-994. doi: 10.1016/j.ajhg.2017.10.006. Epub 2017 Nov 30.


Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

Keywords: bone; bone morphogenetic proteins; congenital heart disease; craniofacial; skeleton.

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 2 / genetics*
  • Bone and Bones / embryology
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 20 / genetics
  • Cleft Palate / genetics
  • Craniofacial Abnormalities / genetics*
  • Developmental Disabilities / genetics*
  • Disease Models, Animal
  • Dwarfism / genetics*
  • Female
  • Haploinsufficiency / genetics*
  • Heart / embryology
  • Heart Defects, Congenital / genetics*
  • Humans
  • Infant
  • Male
  • Mice
  • Mice, Knockout
  • Transforming Growth Factor beta / genetics


  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Transforming Growth Factor beta