Cornelia de Lange syndrome (CdLS, also called Brachmann de Lange syndrome; OMIM 122470) is characterised by pre- and postnatal growth retardation, microcephaly, severe mental retardation with speech delay, feeding problems, major malformations including limb defects, and characteristic facial features.¹ Facial dysmorphism includes arched eyebrows, synophrys, short nose with anteverted nares, long philtrum, thin upper lip, and micrognathia. Although few autosomal dominant forms of CdLS have been described,^2,3 the large majority of cases are sporadic, and the scarcity of these familial forms has hampered the identification of the gene(s) underlying CdLS.⁴ Finally, rare cases of CdLS have been associated with balanced chromosomal translocations.^5–7

A gene responsible for CdLS has been recently identified by two groups. Indeed, Krantz et al performed genome-wide linkage exclusion mapping in 12 CdLS families and identified a locus on chromosome 5p13.⁸ This locus mapped close to both a translocation breakpoint and a small de novo deletion associated with CdLS. Studying the 5p13 translocation breakpoint allowed both groups to identify a disrupted gene which they called NIPBL, for Nipped-B like.^8,9NIPBL is the human homolog of the DrosophilaNipped-B gene, the product of which belongs to the family of chromosomal adherins. The Drosophila Nipped-B protein is involved in chromatid cohesion processes and enhancer-promoter communication.^10,11 The exact function of the human NIPBL gene product, called delangin, is unknown, but its wide expression pattern, including expression in embryonic limb bud, branchial arch, and craniofacial mesenchyme, is consistent with many of the anomalies observed in CdLS. NIPBL mutations have been identified in 20–50% of CdLS cases,^8,9,12 suggesting that some mutations may have escaped detection and/or that CdLS is genetically heterogeneous.

To address this question, we performed a comprehensive clinical, cytogenetic, and molecular study in 14 affected …