Molecular landscape of congenital vertebral malformations: recent discoveries and future directions

Abstract

Vertebral malformations (VMs) pose a significant global health problem, causing chronic pain and disability. Vertebral defects occur as isolated conditions or within the spectrum of various congenital disorders, such as Klippel-Feil syndrome, congenital scoliosis, spondylocostal dysostosis, sacral agenesis, and neural tube defects. Although both genetic abnormalities and environmental factors can contribute to abnormal vertebral development, our knowledge on molecular mechanisms of numerous VMs is still limited. Furthermore, there is a lack of resource that consolidates the current knowledge in this field. In this pioneering review, we provide a comprehensive analysis of the latest research on the molecular basis of VMs and the association of the VMs-related causative genes with bone developmental signaling pathways. Our study identifies 118 genes linked to VMs, with 98 genes involved in biological pathways crucial for the formation of the vertebral column. Overall, the review summarizes the current knowledge on VM genetics, and provides new insights into potential involvement of biological pathways in VM pathogenesis. We also present an overview of available data regarding the role of epigenetic and environmental factors in VMs. We identify areas where knowledge is lacking, such as precise molecular mechanisms in which specific genes contribute to the development of VMs. Finally, we propose future research avenues that could address knowledge gaps.

Keywords: Butterfly vertebrae; Congenital scoliosis; Hemivertebra; Klippel–Feil syndrome; Neural tube defects; Spondylocostal dysostosis; Vertebral defects.

Fig. 1

Schematic representation of vertebral development in human embryo. NT – neural tube. Created with Biorender.com

Fig. 2

Classification of vertebrae malformations based on the segmentation or formation failures. Segmentation defects encompass block vertebra and unilateral unsegmented bar, whereas formation defects include wedge vertebra, hemivertebra, and butterfly vertebra. Hemivertebra is classified into fully segmented, incarcerated, semisegmented, and nonsegmented. Segmentation defects were illustrated using the example of the lumbar spine segment. Created with Biorender.com

Fig. 3

Anteroposterior (A) and lateral (B) cervical spine radiographs showing vertebrae fusion at C6-C7 in a patient with Klippel–Feil syndrome