Congenital vertebral malformations are phenotypically and etiologically heterogeneous. Their estimated incidence is between 0.5 to 1/1000 [1–4]. Vertebral malformations may represent an isolated finding, occur in association with other renal, cardiac, or spinal cord malformations, or occur as part of an underlying chromosome abnormality or syndrome. These include, but are not limited to, hemifacial microsomia, Alagille, Jarcho-Levin, Klippel-Feil, Goldenhar,, basal cell nevus, trisomy 18, diabetic embryopathy and VACTERL (vertebral, cardiac, renal, limb anomalies, anal atresia, tracheo-esophageal fistula) syndromes. Vertebral malformations most commonly include hemivertebrae, vertebral bars, supernumerary vertebrae, butterfly vertebrae, and wedge-shaped vertebrae.
Congenital scoliosis is caused by segmentation defects such as fused vertebrae, vertebral body formation defects, and mixed defects in which both types of lesions are encountered [3, 4]. Each of these conditions may cause development of a spinal curve based on asymmetric growth. The severity of the curve is related to the type of defect and whether or not the primary problem is accompanied by any compensatory developmental changes.
Vertebral segmentation proceeds through a clock and wave front mechanism under Notch signaling control. Negative feedback through the canonical Wnt/β catenin pathway via Axin 2 modulates the process [5, 6]. Based on mouse-human synteny analysis, a series of candidate genes known to cause vertebral malformations in the mouse have been identified [5–8]. One gene, Wnt3a, is necessary for generation of the posterior portion of the neuraxis, as knockout mice fail to develop a tailbud and are truncated from a point slightly anterior to the hindlimbs . This gene is a member of a moderate-sized multigene family comprised of at least 12 members in humans and the mouse. Genes in this family function both in establishing the body plan in development and as potential oncogenes . Wnt3a has been proposed to be a major controlling gene in the oscillation of Notch signaling that is necessary for segmentation to occur .
Since isolated congenital vertebral malformation most often represents a sporadic occurrence within a particular family, it is virtually impossible to utilize traditional linkage approaches to identify causative genes. This makes candidate gene analyses a viable alternative method to study this condition. We hypothesized that mutations in WNT3A may be associated with the development of isolated vertebral malformations and congenital scoliosis. In order to test this hypothesis we undertook a pilot study and performed DNA sequence analysis in a heterogeneous cohort of 50 patients with congenital vertebral malformations.