Spondylocostal dysostosis (SCD) is an inherited disorder that is characterized 
by the presence of extensive hemivertebrae, truncal shortening and abnormally 
aligned ribs. It arises during embryonic development by a disruption of 
formation of somites (the precursor tissue of the vertebrae, ribs and associated 
tendons and muscles). Previously, three genes causing a subset of autosomal 
recessive forms of this disease have been identified: DLL3 (SCDO1: MIM 277300), 
MESP2 (SCDO2: MIM 608681) and LFNG (SCDO3: MIM609813). These genes are all 
important components of the Notch signaling pathway, which has multiple roles in 
development and disease. Here we have used autozygosity mapping to identify a 
mutation in a fourth Notch pathway gene, Hairy-and-Enhancer-of-Split-7 (HES7), 
in an autosomal recessive SCD family. HES7 encodes a bHLH-Orange domain 
transcriptional repressor protein that is both a direct target of the Notch 
signaling pathway, and part of a negative feedback mechanism required to 
attenuate Notch signaling. A missense mutation was identified in the DNA-binding 
domain of the HES7 protein. Functional analysis revealed that the mutant HES7 
was not able to repress gene expression by DNA binding or protein 
heterodimerization. This is the first report of mutation in the human HES7 gene, 
and provides further evidence for the importance of the Notch signaling pathway 
in the correct patterning of the axial skeleton.