Genetics of Cornelia de Lange Syndrome

What causes Cornelia de Lange syndrome?

To read some introductory information about genetics go to the key topics section and select ‘genetics’ from the drop-down menu.

There are different subtypes of Cornelia de Lange syndrome.  These are ‘Classic’, ‘Mild’ and ‘Atypical’ forms of the syndrome.  There may be differences in the genetic mechanism underlying these different subtypes.  However, this is not yet completely understood.

The genetic causes of Cornelia de Lange syndrome (CdLS) are complex and continue to be researched. A change (mutation) in one of the following genes is known to result in Cornelia de Lange syndrome: NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Mutations in BRD4 and ANKRD11 can result in syndromes that overlap with CdLS, however, they are less commonly associated with classical CdLS. Some of the newly identified genes that contribute to the understanding of CdLS include EP300, Aff4, TAF1, ARCN1, ARID1B, ASXL2.

Changes to a gene (NIPBL) on the short arm of chromosome 5 have been found in around 70% of individuals with Cornelia de Lange syndrome. Changes to the other genes are less common (SMC1A = 5%;  HDAC8 = 5%; and SMC3, RAD21, BRD4 and ANKRD11 = below 1%). Research to fully understand all the genetic causes of the syndrome is still ongoing.

Is there a genetic test for Cornelia de Lange syndrome?

CdLS can be diagnosed through clinical observation or by identifying changes in one of five specific genes: NIPBL, SMC1A, SMC3, RAD21, and HDAC8. In some cases, changes in two additional genes, BRD4 and ANKRD11, have also been associated with the syndrome.

The wide range of symptoms and genetic differences in people with mild or “atypical” CdLS can make diagnosis difficult. Variants in the NIPBL gene usually cause the more “classic” form of CdLS, while fewer people (5%–7%) have variants in SMC1A, SMC3, RAD21, and HDAC8, which typically lead to milder forms of CdLS.

Genetic tests for all of the genes associated with Cornelia de Lange syndrome have been developed.  You can ask your General Practitioner (also known as Primary Healthcare Physician) for a referral to a clinical geneticist if you feel it would be useful to discuss the possibility of testing for your child with Cornelia de Lange syndrome.  Genetic testing is not always appropriate or necessary (particularly if your doctor is very certain about the clinical diagnosis).

If your child is tested it is important to remember that the genetic changes on chromosome 5 (NIPBL mutations) that cause Cornelia de Lange syndrome have only been found in around 70% of individuals with the syndrome, and this percentage is lower in people who are mildly affected.  Limitations in genetic testing technology means that not all changes on chromosome 5 will be found and changes to other genes may be the cause.  In a proportion of individuals with Cornelia de Lange syndrome the genetic change is not present in the blood DNA and testing of other tissues, such as skin, may be required.