Abstract
Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features1,2,3. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur2. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster5.
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Acknowledgements
We thank the individuals with CdLS and their families for their support and willingness to donate samples; the Cornelia de Lange Syndrome Foundation, their staff and their director J. Mairano for their support; and N. Spinner, M. Jackson, A. Kline, J. Morrissette, M. Budarf and the staff of the clinical cytogenetics laboratory and the sequencing core at The Children's Hospital of Philadelphia for their comments and guidance. This work was supported by grants from the National Institutes of Health, National Institute of Child Health and Human Development (to I.D.K., M.D., A.D.L. and A.L.C.).
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Krantz, I., McCallum, J., DeScipio, C. et al. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet 36, 631–635 (2004). https://doi.org/10.1038/ng1364
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DOI: https://doi.org/10.1038/ng1364
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