A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly

Am J Hum Genet. 2002 Feb;70(2):547-55. doi: 10.1086/338921. Epub 2002 Jan 3.


Studies in mouse and chick have shown that the 5' HoxD genes play major roles in the development of the limbs and genitalia. In humans, mutations in HOXD13 cause the dominantly inherited limb malformation synpolydactyly (SPD). Haploinsufficiency for the 5' HOXD genes has recently been proposed to underlie the monodactyly and penoscrotal hypoplasia in two children with chromosomal deletions encompassing the entire HOXD cluster. Similar deletions, however, have previously been associated with split-hand/foot malformation (SHFM), including monodactyly. Here we report a father and daughter with SPD who carry a 117-kb microdeletion at the 5' end of the HOXD cluster. By sequencing directly across the deletion breakpoint, we show that this microdeletion removes only HOXD9-HOXD13 and EVX2. We also report a girl with bilateral split foot and a chromosomal deletion that includes the entire HOXD cluster and extends approximately 5 Mb centromeric to it. Our findings indicate that haploinsufficiency for the 5' HOXD genes causes not SHFM but SPD and point to the presence of a novel locus for SHFM in the interval between EVX2 and D2S294. They also suggest that there is a regulatory region, upstream of the HOXD cluster, that is responsible for activating the cluster as a whole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chromosome Breakage / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Female
  • Foot Deformities, Congenital / genetics
  • Foot Deformities, Congenital / physiopathology
  • Hand Deformities, Congenital / genetics
  • Hand Deformities, Congenital / physiopathology
  • Haplotypes / genetics
  • Homeodomain Proteins / genetics*
  • Humans
  • Limb Deformities, Congenital / genetics*
  • Limb Deformities, Congenital / physiopathology*
  • Male
  • Molecular Sequence Data
  • Multigene Family / genetics
  • Neoplasm Proteins / genetics*
  • Pedigree
  • Phenotype
  • Sequence Deletion / genetics*
  • Transcription Factors*


  • DNA-Binding Proteins
  • HOXD13 protein, human
  • HOXD9 protein, human
  • Homeodomain Proteins
  • Hoxd9 protein, mouse
  • Neoplasm Proteins
  • Transcription Factors

Associated data

  • GENBANK/AA620964
  • GENBANK/AB051502
  • GENBANK/AC004080
  • GENBANK/AC009336
  • GENBANK/AC015584
  • GENBANK/AC016915
  • GENBANK/AF224263
  • GENBANK/AF415204
  • GENBANK/AI214712
  • GENBANK/D61190