Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome

Hum Mutat. 2013 Dec;34(12):1589-96. doi: 10.1002/humu.22430. Epub 2013 Sep 16.


Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism, and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21, and HDAC8 and one proband was found to carry a mutation in SMC3. To date, 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations, and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This article reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype.

Keywords: Cornelia de Lange syndrome; HDAC8; NIPBL; RAD21; SMC1A; SMC3.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Cell Cycle Proteins / genetics
  • Chondroitin Sulfate Proteoglycans / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • DNA-Binding Proteins
  • De Lange Syndrome / diagnosis
  • De Lange Syndrome / genetics*
  • Facies
  • Gene Expression
  • Genetic Association Studies*
  • Genotype*
  • Humans
  • Mutation*
  • Nuclear Proteins / genetics
  • Phenotype*
  • Phosphoproteins / genetics
  • Proteins / genetics


  • Cell Cycle Proteins
  • Chondroitin Sulfate Proteoglycans
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • NIPBL protein, human
  • Nuclear Proteins
  • Phosphoproteins
  • Proteins
  • RAD21 protein, human
  • SMC3 protein, human
  • cohesins
  • structural maintenance of chromosome protein 1