Cornelia de Lange syndrome (CdLS; OMIM #122470, #300590, and #610759), also known as Brachmann-de Lange syndrome, is a genetically heterogeneous disorder affecting multiple aspects of development. The phenotype is distinctively recognizable but may be highly variable in its expression (). This variability is highlighted by the earliest reports of this entity by Vrolik in 18491
and Brachmann in 19162
, who both reported isolated cases of severely affected infants, and in 1933 by de Lange3
who reported two unrelated children with milder manifestations and classified the clinical findings as a diagnostic entity.
Phenotypic spectrum in CdLS
Affected individuals typically show slow pre- and postnatal growth, and varying degrees of developmental delays and mental retardation at times associated with autistic features.4-8
Almost all organ systems can be affected, but typical involvement includes the craniofacial structures, upper extremities, eyes, gastrointestinal system, hearing and to a lesser degree the heart, diaphragm and genitourinary system.4,5,8,9
The main facial characteristics include arched eyebrows, synophrys, ptosis, long eyelashes, microcephaly, anteverted nares, long philtrum and thin upper lip with micrognathia (). In spite of the considerable differences in severity from patient to patient, the consistent facial dysmorphisms have provided the most helpful feature in establishing a diagnosis. The limbs are involved to variable degrees, primarily affecting the ulnar aspects of the upper limbs, and can range from severe reduction defects with almost complete absence of the forearms to small hands with fifth finger clinodactyly and proximally placed thumbs. Hirsutism is commonly seen especially of the face, neck, back and arms. Gastrointestinal issues include reflux, which is almost universally present and malrotation seen in approximately 25%. Cryptorchidsm and hypospadias are commonly seen in affected males.
Developmental delays and mental retardation are close to universal and generally moderate to severe, however with increasing recognition of the milder CdLS phenotype more and more individuals are being identified with mild cognitive delays. Growth is generally retarded with prenatal onset and mean adult heights in males is 156 cm and 131 cm in females.10
Aided by the molecular analysis described below, it has recently been recognized that there are many mild cases of CdLS that display primarily mental retardation without substantial structural differences. This suggests that the brain is the organ most sensitive to the perturbations of sister chromatid cohesion factors described below. This has prompted development of scoring systems to help anticipate the care that will be required in individual cases.8
The recognition of CdLS as a genetically heterogeneous disorder with genotype-phenotype correlation has arisen from breakthroughs in identifying the multiple genes responsible, all of which are involved in sister chromatid cohesion. Most CdLS cases are sporadic and dominant. At least half are caused by loss-of-function mutations in the Nipped-B-Like (NIPBL)
gene on chromosome 5.6,11-16
Genotype-phenotype correlations with a large number of patients indicate that more severe NIPBL
mutations (such as deletions or truncations) usually cause more severe clinical manifestations than missense mutations. In the mildest forms, affected individuals generally have mild to moderate mental retardation and, at least at a young age, typical facial characteristics ().
The fact that NIPBL
mutations could be identified in only about half the cases of CdLS prompted investigators to look for mutations in other genes with related functions. As described in detail below, NIPBL is required for binding of the cohesin complex that mediates sister chromatid cohesion to chromosomes.17
Thus initial efforts to find other genes responsible for CdLS focused on genes involved in the cohesin complex and its regulation.
Cohesin, which is conserved from fungi to man, consists of the Smc1, Smc3, and Stromalin (SA, Stag) proteins, and has a ring-like structure ().17-20
The internal diameter of the cohesin ring is estimated to be some 35 nm, and a leading model is that cohesin encircles both sister chromatids to hold them together topologically ().18,19,21
Alternatives include “handcuff” models, in which a cohesin ring that encircles one sister interacts or interlocks with a cohesin ring encircling the other. In a third idea, cohesin encircling one sister can interact with proteins bound to the other.22
All the leading models involve topological binding, and the demonstration that cohesin can be released from a yeast circular chromosome by linearizing the DNA provides convincing evidence for this idea.23,24
The cohesin complex and regulatory factors
Screening of large cohorts of individuals with a clinical diagnosis of CdLS in whom NIPBL
mutations were not found revealed that in approximately 5% missense or small in-frame deletion alleles in SMC1A
, which encodes the SMC1 subunit of mitotic cohesin were causative.25-27
One individual with a 3 bp deletion in the SMC3
gene, which encodes another cohesin subunit, was also reported.26
The cases caused by mutations affecting the cohesin subunits are on the mild end of the CdLS spectrum, showing primarily mild to moderate mental retardation without severe limb or other systemic involvement. Growth also appears to be less impacted by mutations in these two structural genes. The SMC1A
gene is X-linked, and both hemizygous male patients, and heterozygous female patients have been found. This gene was found to escape inactivation on the inactivated X chromosome in female mice.28 SMC3
is on chromosome 10, and the mutation is heteroallelic with a wild-type allele.
Combined, mutations in NIPBL, SMC1A and SMC3 have been identified in nearly 60% of CdLS patients with a confident clinical diagnosis. It is possible that mutations affecting the remaining structural components of the cohesin complex [Rad21 or Stag2 (SA)] might occur in some of the patients in which NIPBL, SMC1A or SMC3 mutations have not been found, but these genes have not been extensively screened. There might also be mutations in regulatory sequences for NIPBL. As discussed below, there are also other factors besides NIPBL and cohesin that are required for sister chromatid cohesion, and thus could also be potential candidate genes for CdLS. Finally, evidence outlined in a later section strongly suggests that the developmental deficits seen in CdLS likely result from effects on gene expression, and mutations in some of the genes targeted by NIPBL and cohesin could give rise to similar patient phenotypes. Below we discuss in more detail molecular aspects of cohesin and factors that regulate cohesin, and their potential involvement in CdLS.