NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations

Am J Hum Genet. 2004 Oct;75(4):610-23. doi: 10.1086/424698. Epub 2004 Aug 18.

Abstract

The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cell Cycle Proteins
  • Conserved Sequence / genetics
  • DNA Mutational Analysis
  • De Lange Syndrome / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Molecular Sequence Data
  • Mutation / genetics*
  • Phenotype*
  • Polymorphism, Genetic*
  • Proteins / genetics*
  • Sequence Alignment

Substances

  • Cell Cycle Proteins
  • NIPBL protein, human
  • Proteins