The study of homeotic-transformation mutants in model organisms such as 
Drosophila revolutionized the field of developmental biology, but how these 
mutants relate to human developmental defects remains to be elucidated. Here, we 
show that Liebenberg syndrome, an autosomal-dominant upper-limb malformation, 
shows features of a homeotic limb transformation in which the arms have acquired 
morphological characteristics of a leg. Using high-resolution array comparative 
genomic hybridization and paired-end whole-genome sequencing, we identified two 
deletions and a translocation 5' of PITX1. The structural changes are likely to 
remove active PITX1 forelimb suppressor and/or insulator elements and thereby 
move active enhancer elements in the vicinity of the PITX1 regulatory landscape. 
We generated transgenic mice in which PITX1 was misexpressed under the control 
of a nearby enhancer and were able to recapitulate the Liebenberg phenotype.