A severe, polarized defect in limb development is associated with hemizygosity for the human HOXD cluster

Vertebrates have four clusters of Hox genes (HoxA, HoxB, HoxC, HoxD). A variety of expression and mutant studies indicate that posterior members of the HoxA and HoxD clusters play an important role in vertebrate limb development. In humans, mutation in HOXD13 and HOXA13 have been associated with type II syndactyly or synpolydactyly, and the hand-foot-genital syndrome, respectively. We have investigated two unrelated children with a previously unreported pattern of severe developmental defects on the anterior-posterior (a-p) limb axis and the genetalia, consisting of a single bone in the zeugopod, monodactyly in the autopod of all four limbs, and penoscrotal hypoplasia. Using polymorphic tetranucleotide repeat markers and Southern hybridization studies, we have demonstrated that both children are heterozygous for a deletion that eliminates at least 8 of the 9 genes in the HOXD cluster (HOXD3-HOXD13). In both cases, the deletion has occurred in the paternally inherited chromosome 2. One of the fathers is the carrier of a balanced rearrangement involving 2q31.1, the second father has normal chromosomes. We propose that the patients' phenotypes are due in part to haploinsuficiency for HOXD cluster genes. This hypothesis is supported by the expression patterns of these genes in early vertebrate embryos, as well as the phenotypes of mouse mutants for several HoxD genes. These cases represent the only examples of heterozygous deficiency for a Hox cluster in vertebrates, and suggest that dosage ofhuman HOXD genetic function is crucial for normal growth and patterning of the limbs along the a-p axis.