Members of DISCO are dedicated to uncovering risk factors and potential pathogenic mechanisms of scoliosis. Based on these findings, they aim to develop more effective clinical diagnostic strategies and intervention methods.

Nan Wu/Terry Jianguo Zhang/Zhihong Wu reveal the genetic architecture of congenital vertebral malformations associated with spine development

Nan Wu/Terry Jianguo Zhang/Zhihong Wu reveal the genetic architecture of congenital vertebral malformations associated with spine development

The incidence of congenital vertebral malformations is 0.13 to 0.50 per 1,000 live births, exhibiting significant locus heterogeneity and a complex genetic structure. On February 6, 2024, a collaborative study by Wu Nan, Zhang Jianguo, and Wu Zhihong from the Chinese Academy of Medical Sciences/Peking Union Medical College was published in Nature Communications, titled “Unraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine.” This study analyzed exome/genome sequencing data from 873 probands with congenital vertebral malformations and 3,794 control individuals. Clinical interpretation identified Mendelian causes in 12.0% of the probands and revealed disease mechanisms related to muscle disorders.

The genetic burden testing of ultra-rare variants can identify risk genes with significant effect sizes (such as ITPR2, TBX6, TPO, H6PD, and SEC24B). To further explore the biological relevance of the genetic association signals, single-nucleus RNA sequencing was conducted on the human embryonic spine. The burden testing signals were enriched in the notochord during early development and in myoblasts/myocytes during later stages, highlighting their crucial roles in spinal development. This research provides insights into the developmental biology of the human spine and the pathogenesis of spinal deformities.

Congenital vertebral malformations (CVM) refer to abnormalities in spinal morphology or segmentation, which can lead to progressive spinal deformities and cardiopulmonary dysfunction. The incidence of CVM is approximately 0.13 to 0.50 per 1,000 live births, but this rate may be underestimated due to the asymptomatic nature of many cases. CVM can present as an isolated phenotype, be associated with multisystem abnormalities, or fall within the phenotypic spectrum of chromosomal or Mendelian disorders. In addition to classic Mendelian inheritance, studies have reported compound inheritance of the TBX6 null alleles and risk haplotypes (T-C-A, rs2289292-rs3809624-rs3809627) in patients with hemivertebrae. Interestingly, the risk T-C-A haplotype has a frequency of about 25% in the population, suggesting that CVM has a complex genetic structure, where susceptible genetic variations may range from pathogenic mutations to common low-effect alleles.
The biological mechanisms of congenital vertebral malformations (CVM) are highly heterogeneous, with over 400 pathogenic genes reported (hpo.jax.org/app/browse/term/HP:0003468). Genes associated with CVM are involved in various developmental and homeostatic processes of the skeletal system. For example, TBX6 mediates the segmentation clock during somatic development, leading to the formation of vertebrae and skeletal muscle; SOX9 and RUNX2 are key transcription factors that regulate the differentiation of cartilage and fibrous connective tissue; and NOTCH2 is essential for fundamental cellular processes, with mutations leading to severe developmental defects. Identifying the specific molecular and pathological processes for each patient will facilitate the precise classification and clinical management of CVM. Conversely, mapping all CVM-related genes onto the molecular network of spinal development can reveal the complex processes of embryogenesis.
To systematically investigate the genetic structure and biological basis of congenital vertebral malformations (CVM), the study compiled exome sequencing (ES) or genome sequencing (GS) data from 873 CVM patients and 3,794 control individuals. The research initially performed clinical interpretations to explore the Mendelian genetic susceptibilities underlying CVM, and further utilized alpk3a/b double knockout (DKO) zebrafish models and Alpk3 – / – mouse models to study muscle-related congenital vertebral malformations (CV). For undiagnosed cases, the study conducted gene-based burden testing for ultra-rare variants (URV). Additionally, single-nucleus RNA sequencing (snRNA-seq) was performed on the developing spinal cord of human embryos, integrating expression data with genetic signals to gain deeper insights into the biological relevance of CVM-related genes.
This study highlights the significant role of muscle-related mechanisms in the pathogenesis of congenital vertebral malformations (CVM). The research reports genetic association signals for ultra-rare variants (URV) in CVM. It also demonstrates that the expression of CVM-related genes is enriched in the notochord during early embryonic development and in myoblasts/myocytes during later stages of development. Overall, the study provides a comprehensive depiction of the genetic basis of CVM through cohort-based exome/genome sequencing analysis, covering aspects from Mendelian susceptibility to the structure of rare variants. By integrating genetic signals with single-nucleus RNA sequencing (snRNA-seq) of human embryos, the research reveals key developmental stages and cell types involved in the developing spine.

Deciphering disorders Involving Scoliosis and COmorbidities

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