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

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

Linda Mannini  1 , Francesco Cucco, Valentina Quarantotti, Ian D Krantz, Antonio Musio
Affiliations
Review

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

Linda Mannini et al. Hum Mutat. 2013 Dec.

Abstract

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.

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Conflict of interest statement

Disclosure statement: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Phenotypic characteristics of CdLS caused by mutations in different cohesin regulatory and structural components. A–D: 28-year-old girl with truncating mutation in NIPBL. E–H: 7-year-old boy with missense mutations in NIPBL; I–L: 3-year-old girl with in frame insertion/deletion mutation of HDAC8. M and N: 15-year-old girl with missense mutation in SMC1A. O and P: 3-year-old boy with deletion of RAD21. Q–U: 57-year-old man with in frame deletion of SMC3 (shown as a teenager in “Q”).
Figure 2
Figure 2
Overview of NIPBL mutations. The 47 exons of NIPBL are indicated with black bars. The different domains of NIPBL are indicated: MAU interaction domain (1–300), glutamine rich domain (Gln-rich, 418–462, predicted coiled coil (637–657), undecapeptide repeat PETPKQK(G/S)(E/D)(G/S)R (699–764), nuclear localization signal (NLS, 1,108–1,124), HEAT domain (1,767–2,350) consisting of five repeats (H1: 1,767–1,805, H2: 1,843–1,881, H3: 1,945–1,984, H4: 2,227–2,267, H5: 2,313–2,351).
Figure 3
Figure 3
Genotype–phenotype correlations in CdLS due to NIPBL mutations.
Figure 4
Figure 4
Diagram representing the correlation genotype–phenotype of the five CdLS causative genes.
See this image and copyright information in PMC

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