Congenital vertebral malformation (CVM) in humans affects 1 in 2,000-7,000 live births. The majority of cases are classified as congenital scoliosis, which is a lateral curvature of the spine caused by a small number of structural vertebral defects. Congenital scoliosis may occur in isolation or with congenital defects in other organ systems. More severe forms of vertebral malformation such as spondylocostal dysostosis (SCD) are rare (1 in 100,000 live births), recessively inherited and often affects the entire spine. SCD patients have multiple severe contiguous vertebral defects, including hemivertebra, ribs fusion and rib deletions.
CVM is not usually the result of defective bone formation but rather a failure of an earlier developmental process, termed somitogenesis. During the process of somitogenesis, somites separate from the rostral end of the presomitic mesoderm every 2 hours in mouse and 4–6 hours in human. Somites are the precursors of the vertebrae and also skeletal muscle, tendons, ligaments, and dermis of the back.
Genetic deficits in the mouse can, in isolation or in combination with environmental insult, disrupt somitogenesis and consequently cause vertebral malformations. In order to identify the genetic causes of CVM, we are whole-exome and whole-genome sequencing DNA from patients and their families. I will present our studies of gene-environment interactions in mouse and our recent efforts to identify genes responsible for vertebral defects in CVM patients.