{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:00:43Z","timestamp":1774418443895,"version":"3.50.1"},"reference-count":29,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2009,11,24]],"date-time":"2009-11-24T00:00:00Z","timestamp":1259020800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Clubfoot is a common birth defect that affects 135,000 newborns each year worldwide. It is characterized by equinus deformity of one or both feet and hypoplastic calf muscles. Despite numerous study approaches, the cause(s) remains poorly understood although a multifactorial etiology is generally accepted. We considered the <jats:italic>HOXA<\/jats:italic> and <jats:italic>HOXD<\/jats:italic> gene clusters and insulin\u2010like growth factor binding protein 3 (<jats:italic>IGFBP3<\/jats:italic>) as candidate genes because of their important roles in limb and muscle morphogenesis. Twenty SNPs from the <jats:italic>HOXA<\/jats:italic> and <jats:italic>HOXD<\/jats:italic> gene clusters and 12 SNPs in <jats:italic>IGFBP3<\/jats:italic> were genotyped in a sample composed of non\u2010Hispanic white and Hispanic multiplex and simplex families (discovery samples) and a second sample of non\u2010Hispanic white simplex trios (validation sample). Four SNPs (rs6668, rs2428431, rs3801776, and rs3779456) in the <jats:italic>HOXA<\/jats:italic> cluster demonstrated altered transmission in the discovery sample, but only rs3801776, located in the <jats:italic>HOXA<\/jats:italic> basal promoter region, showed altered transmission in both the discovery and validation samples (<jats:italic>P<\/jats:italic>\u2009=\u20090.004 and 0.028). Interestingly, <jats:italic>HOXA9<\/jats:italic> is expressed in muscle during development. An SNP in <jats:italic>IGFBP3<\/jats:italic>, rs13223993, also showed altered transmission (<jats:italic>P<\/jats:italic>\u2009=\u20090.003) in the discovery sample. Gene\u2013gene interactions were identified between variants in <jats:italic>HOXA<\/jats:italic>, <jats:italic>HOXD<\/jats:italic>, and <jats:italic>IGFBP3<\/jats:italic> and with previously associated SNPs in mitochondrial\u2010mediated apoptotic genes. The most significant interactions were found between <jats:italic>CASP3<\/jats:italic> SNPS and variants in <jats:italic>HOXA<\/jats:italic>, <jats:italic>HOXD<\/jats:italic>, and <jats:italic>IGFBP3<\/jats:italic>. These results suggest a biologic model for clubfoot in which perturbation of <jats:italic>HOX<\/jats:italic> and apoptotic genes together affect muscle and limb development, which may cause the downstream failure of limb rotation into a plantar grade position. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.33130","type":"journal-article","created":{"date-parts":[[2009,11,24]],"date-time":"2009-11-24T19:12:54Z","timestamp":1259089974000},"page":"2745-2752","source":"Crossref","is-referenced-by-count":37,"title":["Altered transmission of <i>HOX<\/i> and apoptotic SNPs identify a potential common pathway for clubfoot"],"prefix":"10.1002","volume":"149A","author":[{"given":"Audrey R.","family":"Ester","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katelyn 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