Monoallelic loss-of-function BMP2 variants result in BMP2-related skeletal dysplasia spectrum

Jessica R C Priestley; Ashish R Deshwar; Harsha Murthy; Maria D D'Agostino; Lucie Dupuis; Balram Gangaram; Christopher Gray; Rebekah Jobling; Emanuela Pannia; Konrad Platzer; Katrina Prescott; Melody Redman; Alyssa L Rippert; Jill A Rosenfeld; Daryl A Scott; Yi W Wang; Zelia Schmederer; Ashwin Dalal; Asodu S Sarma; Cara Skraban; James J Dowling; Roberto Mendoza-Londono; Anne Slavotinek; Elizabeth J Bhoj

doi:10.1016/j.gim.2023.100863

Monoallelic loss-of-function BMP2 variants result in BMP2-related skeletal dysplasia spectrum

Genet Med. 2023 Aug;25(8):100863. doi: 10.1016/j.gim.2023.100863. Epub 2023 Apr 28.

Authors

Jessica R C Priestley¹, Ashish R Deshwar², Harsha Murthy³, Maria D D'Agostino⁴, Lucie Dupuis⁵, Balram Gangaram⁶, Christopher Gray¹, Rebekah Jobling⁷, Emanuela Pannia³, Konrad Platzer⁸, Katrina Prescott⁹, Melody Redman⁹, Alyssa L Rippert¹, Jill A Rosenfeld¹⁰, Daryl A Scott¹¹, Yi W Wang¹², Zelia Schmederer¹³, Ashwin Dalal¹⁴, Asodu S Sarma¹⁴, Cara Skraban¹⁵, James J Dowling¹⁶, Roberto Mendoza-Londono⁵, Anne Slavotinek¹⁷, Elizabeth J Bhoj¹⁸

Affiliations

¹ Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.
² Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
³ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Division of Medical Genetics, Departments of Specialized Medicine and Human Genetics, McGill University Health Center, Montreal, QC, Canada.
⁵ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada.
⁶ Division of Medical Genetics, University of California San Francisco, San Francisco, CA.
⁷ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada; Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁸ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
⁹ Clinical Genetics, The Leeds Teaching Hospital NHS Trust, Leeds, West Yorkshire, United Kingdom.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Baylor Genetics Laboratories, Houston, TX.
¹¹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX.
¹² Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada; Division of Medical Genetics, Departments of Specialized Medicine and Human Genetics, McGill University Health Center, Montreal, QC, Canada.
¹³ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; Medizinisch Genetisches Zentrum, Munich, Germany.
¹⁴ Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
¹⁵ Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
¹⁶ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁷ Division of Medical Genetics, University of California San Francisco, San Francisco, CA; Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH.
¹⁸ Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address: bhoje@chop.edu.

PMID: 37125634
DOI: 10.1016/j.gim.2023.100863

Abstract

Purpose: Bone morphogenic proteins (BMPs) regulate gene expression that is related to many critical developmental processes, including osteogenesis for which they are named. In addition, BMP2 is widely expressed in cells of mesenchymal origin, including bone, cartilage, skeletal and cardiac muscle, and adipose tissue. It also participates in neurodevelopment by inducing differentiation of neural stem cells. In humans, BMP2 variants result in a multiple congenital anomaly syndrome through a haploinsufficiency mechanism. We sought to expand the phenotypic spectrum and highlight phenotypes of patients harboring monoallelic missense variants in BMP2.

Methods: We used retrospective chart review to examine phenotypes from an international cohort of 18 individuals and compared these with published cases. Patient-derived missense variants were modeled in zebrafish to examine their effect on the ability of bmp2b to promote embryonic ventralization.

Results: The presented cases recapitulated existing descriptions of BMP2-related disorders, including craniofacial, cardiac, and skeletal anomalies and exhibit a wide phenotypic spectrum. We also identified patients with neural tube defects, structural brain anomalies, and endocrinopathies. Missense variants modeled in zebrafish resulted in loss of protein function.

Conclusion: We use this expansion of reported phenotypes to suggest multidisciplinary medical monitoring and management of patients with BMP2-related skeletal dysplasia spectrum.

Keywords: BMP2; Bone morphogenic protein; Multiple congenital anomalies; Skeletal dysplasia.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Bone Morphogenetic Protein 2 / genetics
Bone Morphogenetic Proteins
Cell Differentiation
Humans
Osteochondrodysplasias*
Osteogenesis / genetics
Retrospective Studies
Zebrafish* / genetics

Substances

Bone Morphogenetic Proteins
BMP2 protein, human
Bone Morphogenetic Protein 2