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What causes Cornelia de Lange Syndrome

The genetic causes of CdLS are complex and research to fully understand all the genetic causes is still ongoing. The genetic make-up of a child cannot be changed after conception.

The CdLS spectrum has been associated with a change (mutation) in genetic material. Usually, CdLS is caused by a change in one of seven genes. Genes are individual genetic instructions in DNA that make us who we are. The seven genes associated with CdLS are: NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11 (R4). A change in one of these genes affects what is known as the cohesin protein complex (13-18).

The cohesin complex has many functions. One of these includes regulating the process of a fertilised egg dividing many times during the development of a baby. This process requires all of the DNA (genetic material present) to produce a second copy of itself before it divides. Changes to the genetic code can occur when the DNA is copied. The cohesin complex also regulates the expression, structure and organisation of a person’s genetic code (19-22).

If a change in genetic code affects one of the seven genes associated with the CdLS spectrum, the cohesin complex does not function properly. This can cause altered human development and is believed to be the underlying cause of CdLS and syndromes in the CdLS spectrum.

The known causes of CdLS are therefore called cohesinopathies. This is because changes in genes associated with CdLS affect the cohesin complex. However, not all cohesinopathies result in CdLS.

The cohesin complex has multiple parts.  It is thought that there is a core centre which includes a ring which can open to hold the copies of DNA together until they divide, as well as associated proteins which help regulate the core centre. Genes always code for a single protein; in this case each gene related to CdLS codes for a different part of the cohesin protein complex.

Mutations that occur in genes can have small or large effects. There can be single small mutations (missense mutations) that change only a single part of the gene; these tend to produce proteins that might be able to do some of the work but not all, or that do the work slightly differently. Larger or more severe mutations (loss of function mutations) usually lead to more severe effects, such as resulting in no protein being produced at all. Deletions within a single gene, larger than mutations, can result in effects similar to a loss of function mutations or may have more severe effects. Specific gene variants (mutations or deletions in genes) have been identified in up to 84% of individuals with CdLS.

The seven known genes that are implicated in CdLS differ in the clinical features presented (See Table 2 on the following page).


Figure 4 Cornelia de Lange Syndrome (CdLS) is a cohesinopathy (changes in genes associated with CdLS affect the cohesin complex).

Fig. 4 | Cornelia de Lange Syndrome (CdLS) is a cohesinopathy (changes in genes associated with CdLS affect the cohesin complex).

CdLS is caused by genetic variants that affect regulators of the cohesin complex. The structural components form a ring and cohesin subunits (such as STAG 1) attach to the ring and form part of the core complex.


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