Talipes equinovarus is one of the most common congenital musculoskeletal 
anomalies and has a worldwide incidence of 1 in 1000 births. A genetic 
predisposition to talipes equinovarus is evidenced by the high concordance rate 
in twin studies and the increased risk to first-degree relatives. Despite the 
frequency of isolated talipes equinovarus and the strong evidence of a genetic 
basis for the disorder, few causative genes have been identified. To identify 
rare and/or recurrent copy number variants, we performed a genome-wide screen 
for deletions and duplications in 413 isolated talipes equinovarus patients 
using the Affymetrix 6.0 array. Segregation analysis within families and gene 
expression in mouse E12.5 limb buds were used to determine the significance of 
copy number variants. We identified 74 rare, gene-containing copy number 
variants that were present in talipes equinovarus probands and not present in 
759 controls or in the Database of Genomic Variants. The overall frequency of 
copy number variants was similar between talipes equinovarus patients compared 
with controls. Twelve rare copy number variants segregate with talipes 
equinovarus in multiplex pedigrees, and contain the developmentally expressed 
transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, 
CHD (chromodomain protein)1, and RIPPLY2. Although our results do not support a 
major role for recurrent copy number variations in the etiology of isolated 
talipes equinovarus, they do suggest a role for genes involved in early 
embryonic patterning in some families that can now be tested with large-scale 
sequencing methods.