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Abstract
Purpose
Bone morphogenic proteins (BMPs) regulate gene expression related to many critical
developmental processes, including osteogenesis for which they are named. 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 employed retrospective chart review to examine phenotypes from an international
cohort of 18 individuals and compared these to 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 disorder 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.
Conclusions
We use this expansion of reported phenotypes to suggest multidisciplinary medical
monitoring and management of patients with BMP2-related skeletal dysplasia spectrum.
Keywords
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Article info
Publication history
Accepted:
April 18,
2023
Received in revised form:
April 17,
2023
Received:
November 3,
2022
Publication stage
In Press Accepted ManuscriptIdentification
Copyright
© 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
