Clubfoot or idiopathic talipes equinovarus (ITEV) is one of the five most common birth defects, affecting approximately 4,000 newborns each year in the US. While the orthopedic care of these children has improved, longterm problems persist and the health care costs are significant. Studies suggest that ITEV is a complex disorder with segregation analyses and family studies indicating that genetic factors play an important etiologic role in the development of ITEV. Only one environmental factor, maternal smoking during pregnancy, has been implicated. We postulate that a small number of genes account for a substantial fraction of ITEV and that these genes can be identified in a defined population. The challenge now is to identify the genetic loci and, later, the effect of environmental exposures. To accomplish this task, it is important to have a well-defined population and the methodology to detect linkage with and without association. Towards these goals, we have identified and characterized multiplex ITEV families and simplex ITEV trios including two large ITEV families, a resource which is among the largest ITEV population in existence. We will perform a high-density SNP genome scan on our ITEV dataset to identify chromosomal regions that may harbor ITEV genes with subsequent interrogation of these regions and candidate genes. We are in a position with our unique ITEV population and with the methodology in place to undertake this study. The study phases are: 1) continued ascertainment of multiplex families and ethnically diverse parent child trios, 2) high density SNP genome-wide scan 3) collection of confirmatory (simplex trios and case-control) datasets to test newly identified genes. The results of this study will provide data essential to the identification of the gene(s) contributing to the ITEV phenotype. Identification of high-risk genotypes can lead to the development of prevention programs in selected populations and may suggest gene-based prevention strategies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043342-03
Application #
7482335
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Javois, Lorette Claire
Project Start
2006-09-29
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$335,992
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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Lu, W; Bacino, C A; Richards, B S et al. (2012) Studies of TBX4 and chromosome 17q23.1q23.2: an uncommon cause of nonsyndromic clubfoot. Am J Med Genet A 158A:1620-7
Weymouth, Katelyn S; Blanton, Susan H; Bamshad, Michael J et al. (2011) Variants in genes that encode muscle contractile proteins influence risk for isolated clubfoot. Am J Med Genet A 155A:2170-9
Sommer, Amy; Blanton, Susan H; Weymouth, Katelyn et al. (2011) Smoking, the xenobiotic pathway, and clubfoot. Birth Defects Res A Clin Mol Teratol 91:20-8
Ester, Audrey R; Weymouth, Katelyn S; Burt, Amber et al. (2009) Altered transmission of HOX and apoptotic SNPs identify a potential common pathway for clubfoot. Am J Med Genet A 149A:2745-52