J Med Genet 40:333-339 doi:10.1136/jmg.40.5.333
  • Original article

Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis

  1. P D Turnpenny1,2,
  2. N Whittock2,
  3. J Duncan2,
  4. S Dunwoodie3,4,
  5. K Kusumi5,
  6. S Ellard2
  1. 1Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK
  2. 2Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
  3. 3Developmental Biology Unit, Victor Chang Cardiac Research Institute, St Vincent’s Hospital, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
  4. 4Department of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2033, Australia
  5. 5Department of Paediatrics, The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318, USA
  1. Correspondence to:
 Dr P D Turnpenny, Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter EX2 5DW, UK; 
  • Accepted 11 February 2003
  • Revised 10 February 2003


The spondylocostal dysostoses (SCD) are a group of disorders characterised by multiple vertebral segmentation defects and rib anomalies. SCD can either be sporadic or familial, and can be inherited in either autosomal dominant or recessive modes. We have previously shown that recessive forms of SCD can be caused by mutations in the delta-like 3 gene, DLL3. Here, we have sequenced DLL3 in a series of SCD cases and identified 12 mutations in a further 10 families. These include 10 novel mutations in exons 4–8, comprising nonsense, missense, frameshift, splicing, and in frame insertion mutations that are predicted to result in either the truncation of the mature protein in the extracellular domain, or affect highly conserved amino acid residues in the epidermal growth factor-like repeats of the protein. The affected cases represent diverse ethnic backgrounds and six come from traditionally consanguineous communities. In all affected subjects, the radiological phenotype is abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which we suggest the term “pebble beach sign”. This is a very consistent phenotype-genotype correlation and we suggest the designation SCD type 1 for the AR form caused by mutations in the DLL3 gene.