A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.

In 1982, one of us reported a cluster of eight individuals affected by spondylocostal dysostosis (SD, MIM 277300) in four nuclear families indigenous to a village from eastern Switzerland. We tested the hypothesis that the molecular basis for this cluster was segregation of a single mutation in the DLL3 gene, recently linked to SD. Marker haplotypes around the DLL3 locus contradicted this hypothesis as three different haplotypes were seen in affected individuals, but sequence analysis showed that three unreported DLL3 mutations were segregating: a duplication of 17 bp in exon 8 (c.1285-1301dup), a single-nucleotide deletion in exon 5 (c.615delC), and a R238X nonsense mutation in exon 6. Contrary to our initial assumption of a single allele segregating in this small community, three different pathogenic alleles were observed, with a putative founder mutation occurring at the homozygous state but also compounding with, and thus revealing, two other independent mutations. As all three mutations predict truncation of the DLL3 protein and loss of the membrane-attaching domain, the results confirm that autosomal recessive spondylocostal dysostosis represents the null phenotype of DLL3, with remarkable phenotypic consistency across families.