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

• Published in: Journal of medical genetics Vol. 40; no. 5; pp. 333 - 339
• Main Authors: Turnpenny, P D, Whittock, N, Duncan, J, Dunwoodie, S, Kusumi, K, Ellard, S
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.05.2003; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Abnormalities; Adult; Amino acids; Biological and medical sciences; Consanguinity; Continental Population Groups - genetics; Diseases of the osteoarticular system; DLL3; DNA Mutational Analysis; Dysostoses - diagnostic imaging; Dysostoses - embryology; Dysostoses - genetics; Dysostoses - metabolism; Epidermal growth factor; Exons - genetics; Fetus - metabolism; Gene mutations; Genetic aspects; Genotype & phenotype; Haplotypes - genetics; Humans; Infant; Intracellular Signaling Peptides and Proteins; Ligands; Ligands (Biochemistry); Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mutation; Mutation - genetics; Notch signalling pathway; Original; Phenotype; Physiological aspects; Polymorphism, Genetic - genetics; Radiography; Receptors, Notch; Signal Transduction; somitogenesis; Spine - abnormalities; Spondyloarthropathies; spondylocostal dysostosis; Vertebrae; Spondylocostal dysostosis; Human; Gene; Segmentation; Ligand; Diseases of the osteoarticular system; Action potential; Mutation; Genetic determinism
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.40.5.333

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.