title: Deletions of 5' HOXC genes are associated with lower extremity malformations, including clubfoot and vertical talus.
abstract: BACKGROUND
  Deletions of the HOXC gene cluster result in variable phenotypes in mice, but have been rarely described in humans.
  
  
  OBJECTIVE
  To report chromosome 12q13.13 microdeletions ranging from 13 to 175 kb and involving the 5' HOXC genes in four families, segregating congenital lower limb malformations, including clubfoot, vertical talus and hip dysplasia.
  
  
  METHODS
  Probands (N=253) with clubfoot or vertical talus were screened for point mutations and copy number variants using multiplexed direct genomic selection, a pooled BAC targeted capture approach. SNP genotyping included 1178 probands with clubfoot or vertical talus and 1775 controls.
  
  
  RESULTS
  The microdeletions share a minimal non-coding region overlap upstream of HOXC13, with variable phenotypes depending upon HOXC13, HOXC12 or the HOTAIR lncRNA inclusion. SNP analysis revealed HOXC11 p.Ser191Phe segregating with clubfoot in a small family and enrichment of HOXC12 p.Asn176Lys in patients with clubfoot or vertical talus (rs189468720, p=0.0057, OR=3.8). Defects in limb morphogenesis include shortened and overlapping toes, as well as peroneus muscle hypoplasia. Finally, HOXC and HOXD gene expression is reduced in fibroblasts from a patient with a 5' HOXC deletion, consistent with previous studies demonstrating that dosage of lncRNAs alters expression of HOXD genes in trans.
  
  
  CONCLUSIONS
  Because HOXD10 has been implicated in the aetiology of congenital vertical talus, variation in its expression may contribute to the lower limb phenotypes occurring with 5' HOXC microdeletions. Identification of 5' HOXC microdeletions highlights the importance of transcriptional regulators in the aetiology of severe lower limb malformations and will improve their diagnosis and management.
authors.affiliation: Department of Orthopedic Surgery, Washington University, St. Louis, Missouri, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Alvarado
authors.affiliation: Department of Orthopedic Surgery, Washington University, St. Louis, Missouri, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: McCall
authors.affiliation: Department of Pediatrics, University of Texas Medical School, Houston, Texas, USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.affiliation: Department of Orthopedic Surgery, Washington University, St. Louis, Missouri, USA Shriners Hospital for Children, St Louis, Missouri, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Dobbs
authors.affiliation: Department of Orthopedic Surgery, Washington University, St. Louis, Missouri, USA Department of Neurology, Washington University, St. Louis, Missouri, USA Department of Pediatrics, Washington University, St. Louis, Missouri, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
mesh_terms: D000818:Animals; D002881:Chromosomes, Human, Pair 12; D003025:Clubfoot / Q000235:genetics* / Q000473:pathology; D005121:Extremities / Q000473:pathology; D005260:Female; D005413:Flatfoot / Q000235:genetics* / Q000473:pathology; D017353:Gene Deletion; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C561566:HOTAIR long untranslated RNA, human; C410305:HOXC13 protein, human; D018398:Homeodomain Proteins; C469340:Hoxc12 protein, mouse; D062085:RNA, Long Noncoding
keywords: Clubfoot; Copy-number; Vertical Talus