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

Abstract

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.

Comparative population genomic analysis uncovers novel genomic footprints and genes associated with small body size in Chinese pony

“…This protein belongs to the TGF-β superfamily, which has diverse biological activities related to bone physiology and metabolism [22,23]. Previous studies have found associations of the BMP-2 variants with bone and cardiac development, bone mineral density, as well as body size traits [24,25]. Also in human, BMP-2 appears to be the most important BMP affecting the adult skeleton [44].…”

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide

“…Seven homozygous KI mice, from different litters, survived past weaning age and were subjected to further evaluation for gross phenotypic and skeletal changes. We performed computerized tomography (µCT) whole-body scans of heterozygous ( Col27a1 G682R/+ ) and homozygous ( Col27a1 G682R/G682R ) KI mice and WT littermates to evaluate for gross skeletal abnormalities and reduced body length as a surrogate for the short stature phenotype observed in the human subjects [ 27 ]. We measured the snout to base of the tail (at caudal vertebra 4, CA4) distance to evaluate differences in body length among the heterozygous, homozygous, and WT mice.…”

Comparative population genomic analysis uncovers novel genomic footprints and genes associated with small body size in Chinese pony

“…This protein belongs to the TGF-β superfamily, which has diverse biological activities related to bone physiology and metabolism [17,18]. Previous studies have found associations of the BMP-2 variants with bone and cardiac development, bone mineral density, as well as body size traits [19,20]. Also in human, BMP-2 appears to be the most important BMP affecting the adult skeleton [21].…”