Nonsynonymous WNT3A Mutation in a Patient with Congenital Scoliosis

Prior investigations have not identified a major locus for congenital vertebral malformations, providing evidence that there is clinical and 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 and accessory neural tubes. Because congenital vertebral malformations represent a sporadic occurrence, linkage approaches to identify genes associated with human vertebral development are not feasible. Based on the observations in the mouse, we hypothesized that WNT3A mutations might account for a subset of human congenital scoliosis. We therefore performed DNA sequence analysis of the WNT3A gene in 50 patients with congenital vertebral malformations spanning the entire vertebral column. A female patient with a T12-L1 hemivertebrae was found to be heterozygous for a GCC -->ACC missense mutation resulting in the substitution of alanine by threonine at codon 134 in exon 3 (UCSC position ch1:224,545,178 May 2004 assembly) of the WNT3A gene. This entire exon is highly conserved. The father of the patient who is clinically asymptomatic was also heterozygous for the missense mutation. The mutation was not found in a control population of 85 anonymized individuals (81 Caucasians, 2 Hispanics and 2 Asians). Since this mutation was not observed in a control population, and leads to a non-conservative amino acid change, we conclude that this mutation is likely to be clinically significant. Several established mechanisms can explain the existence of the mutation in both the patient and her asymptomatic father. Documenting the absence of the mutation in a larger control population or documenting a functional difference in WNT3A function would provide further evidence supporting its pathogenicity.