Lack of evidence of WNT3A as a candidate gene for congenital vertebral malformations
1 Molecular Diagnostic Research Laboratory, Marshfield Clinic, Marshfield, Wisconsin, USA
2 Department of Pediatric Orthopedics, Hospital for Special Surgery, New York, New York, USA
3 University of Wisconsin Medical School, Madison, Wisconsin, USA and Geriatrics Research, Education, and Clinical Center, William S. Middleton Veterans Administration Medical Center, Madison, Wisconsin, USA
4 Department of Medical Genetic Services, Marshfield Clinic, Marshfield, Wisconsin, USA
5 Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA
6 Office of Scientific Writing and Publications, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA
7 Department of Orthopedic Spine Surgery, Marshfield Clinic, Marshfield, Wisconsin, USA
8 University of Wisconsin-Madison, Clinical Genetic Center, Madison, Wisconsin, USA
9 Adult and Pediatric Spine Surgery, Hospital for Special Surgery, New York, New York, USA
Scoliosis 2007, 2:13 doi:10.1186/1748-7161-2-13Published: 23 September 2007
Prior investigations have not identified a major locus for vertebral malformations, providing evidence that there is genetic heterogeneity for this condition. WNT3A has recently been identified as a negative regulator of Notch signaling and somitogenesis. Mice with mutations in Wnt3a develop caudal vertebral malformations. Because congenital vertebral malformations represent a sporadic occurrence, linkage approaches to identify genes associated with human vertebral development are not feasible. We hypothesized that WNT3A mutations might account for a subset of congenital vertebral malformations.
A pilot study was performed using a cohort of patients with congenital vertebral malformations spanning the entire vertebral column was characterized. DNA sequence analysis of the WNT3A gene in these 50 patients with congenital vertebral malformations was performed.
A female patient of African ancestry with congenital scoliosis and a T12-L1 hemivertebrae was found to be heterozygous for a missense variant resulting in the substitution of alanine by threonine at codon 134 in highly conserved exon 3 of the WNT3A gene. This variant was found at a very low prevalence (0.35%) in a control population of 443 anonymized subjects and 1.1% in an African population.
These data suggest that WNT3A does not contribute towards the development of congenital vertebral malformations. Factors such as phenotypic and genetic heterogeneity may underlie our inability to detect mutations in WNT3A in our patient sample.