Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions PMID: 29198724

RQC and Longevity Regulation

2026-09-03

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.

Tiong Yang Tan ¹ , Claudia Gonzaga-Jauregui ² , Elizabeth J Bhoj ³ , Kevin A Strauss ⁴ , Karlla Brigatti ⁴ , Erik Puffenberger ⁴ , Dong Li ³ , LiQin Xie ⁵ , Nanditha Das ⁵ , Ioanna Skubas ⁵ , Ron A Deckelbaum ⁵ , Virginia Hughes ⁵ , Susannah Brydges ⁵ , Sarah Hatsell ⁵ , Chia-Jen Siao ⁵ , Melissa G Dominguez ⁵ , Aris Economides ⁵ , John D Overton ² , Valerie Mayne ⁶ , Peter J Simm ⁷ , Bryn O Jones ⁸ , Stefanie Eggers ⁹ , Gwenaël Le Guyader ¹⁰ , Fanny Pelluard ¹¹ , Tobias B Haack ¹² , Marc Sturm ¹² , Angelika Riess ¹² , Stephan Waldmueller ¹³ , Michael Hofbeck ¹⁴ , Katharina Steindl ¹⁵ , Pascal Joset ¹⁵ , Anita Rauch ¹⁵ , Hakon Hakonarson ³ , Naomi L Baker ¹⁶ , Peter G Farlie ¹⁶

Affiliations

1. Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia; Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: [email protected].
2. Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
3. Center for Applied Genomics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4399, USA.
4. Clinic for Special Children, Philadelphia, PA 17579, USA.
5. Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
6. Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia.
7. Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia; Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia.
8. Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Royal Children's Hospital, Parkville, Melbourne, VIC 3052, Australia.
9. Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
10. Department of Medical Genetics, Poitiers University Hospital, Poitiers 86021, France.
11. Department of Pathology, Bordeaux University Hospital, Bordeaux 33076, France.
12. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.
13. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany; Universitätsklinik für Kinder- und Jugendmedizin, Kinderheilkunde II Kardiologie Intensivmedizin Pulmologie, 72076 Tuebingen, Germany.
14. Universitätsklinik für Kinder- und Jugendmedizin, Kinderheilkunde II Kardiologie Intensivmedizin Pulmologie, 72076 Tuebingen, Germany.
15. Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.
16. Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia.

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.

Keywords

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