Cornelia de Lange syndrome (CdLS) is a multiple malformation disorder characterized by dysmorphic facial features, mental retardation, growth delay and limb reduction defects 1,2 . We indentified and characterized a new gene, NIPBL, that is mutated in individuals with CdLS and determined its structure and the structures of mouse, rat and zebrafish homologs. We named its protein product delangin. Vertebrate delangins have substantial homology to orthologs in flies, worms, plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B. We propose that perturbed delangin function may inappropriately activate DLX genes, thereby contributing to the proximodistal limb patterning defects in CdLS. Genome analyses typically identify individual delangin or Nipped-Blike orthologs in diploid animal and plant genomes. The evolution of an ancestral sister chromatid cohesion protein to acquire an additional role in developmental gene regulation suggests that there are parallels between CdLS and Roberts syndrome.The multisystem nature of the CdLS phenotype suggests that it is caused by a microdeletion or microduplication affecting several genes or by a single gene that regulates various target genes. A high-density BAC microarray comparative genome hybridization screen found no evidence for a consistent pattern of microdeletion or microduplication 3 . Because CdLS is rare and most cases are sporadic, genome-wide linkage screens are problematic. As an alternative, we analyzed chromosomal breakpoints associated with CdLS, focusing first on three classical cases with de novo balanced translocations, including the previously described translocations t(3;17)(q26.3;q23.1) 4 and t(14;21)(q32;q11) 5 . We first analyzed the 3q26.3 breakpoint because of NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome Arrows indicate the normal chromosome 5 and the der(5) t(5;13)(p13.1;q12.1) and der(13) t(5;13)(p13.1;q12.1) chromosomes. In occasional metaphases a weak G248P84262B4 signal can be detected on the der(5) chromosome as well as a strong signal on the der(13). The combined data suggest that the most likely location for the breakpoint is close to the proximal end of the region of overlap for inserts of G248P84262B4 and G248P8840C10 (Fig. 2a).