How is Cornelia de Lange Syndrome Diagnosed?

How is Cornelia de Lange Syndrome Diagnosed?


Can CdLS be diagnosed prenatally (before birth)?

There are several indicators that can lead to diagnosis of CdLS prenatally (before birth). Indicators may include parents with an earlier child with CdLS, or a new pregnancy in a family with a known genetic change in a gene associated with CdLS.

Another indicator may be no family history but features suggestive of CdLS on an ultrasound scan of an unborn baby.

Prenatal features suggestive of CdLS may include:

  • Intrauterine growth restriction (IUGR)
    IUGR is a condition in which a baby’s growth slows or stops during pregnancy. It is the most common suggestive feature of CdLS in a developing baby and typically begins in the second trimester (months 4 to 6) of pregnancy (50).
  • Prenatal limb differences
    E.g. Small hands and feet and/or missing portions or shortening of limbs.
  • Abnormal facial profile
    E.g. An undersized jaw (micrognathia) or protruding upper jaw (prominent maxilla) (51).
  • Increased nuchal thickness
    A collection of fluid under the skin at the back of a baby’s neck.
  • Diaphragmatic hernia
    A hole in the diaphragm, the muscles under the lungs that is responsible for breathing. The hole allows organs from the abdomen to move into the chest.
  • Cardiac malformation
    Heart defects (50).

If an ultrasound scan reveals features suggestive of a genetic disorder, a midwife or doctor will discuss the possible benefits and risks of prenatal genetic testing with the baby’s parents. The midwife or doctor will help parents to make a decision about the investigations that are available (R7).

If parents have a previous child with CdLS or there is a family member with a known change in a gene associated with CdLS, a midwife or doctor will discuss the possible benefits and risks of prenatal genetic testing.
Prenatal genetic testing can be carried out using DNA from samples of cells from the placenta (the organ linking the mother’s blood supply with the developing baby) or amniotic fluid (the fluid that surrounds the developing baby in the womb). Genetic testing can identify changes in any of the seven genes that are associated with CdLS (R8).

The tests can help parents make choices about further tests, care or treatment during the pregnancy or after the baby is born. It is important to remember that any prenatal test offered is optional. It is up to the family to decide whether any tests that are offered would be helpful or wanted.

The newest prenatal screening test, non-invasive cell-free foetal DNA (also called non-invasive prenatal screening or NIPS) can screen for various genetic changes in the developing baby in the mother’s blood. This might detect changes in genes that could cause CdLS. In families with a previous child with CdLS and a known mutation, this test may be a useful way to examine the specific gene that may be affected. However, in families without a previous child with CdLS, the result would be difficult or impossible to determine with accuracy, and would likely need extensive interpretation. Mosaicism also cannot be assessed using this testing method. This means this type of testing may not be useful for CdLS.

Genetic Testing for the CdLS Spectrum (post birth)

Genetic tests have been developed to identify changes in any of the genes associated with the CdLS spectrum. A referral to a clinical geneticist can be made if parents feel that it would be useful to discuss the possibility of testing for the child with a CdLS spectrum syndrome. Genetic testing is not always appropriate or necessary (particularly if a doctor is very certain about the clinical diagnosis), but would be the only way to approach prenatal testing for future pregnancies.

Panel Sequencing

The most effective genetic test to identify a change in a gene known to cause CdLS is panel sequencing. Panel sequencing analyses multiple genes at once. When testing for CdLS spectrum the panel should include at least the seven known CdLS genes (see Figure 5 ). Most laboratories for genetic testing will include additional genes that can cause a phenotype resembling CdLS, such as CREBBP and EP300.

Sanger Sequencing

Although panel sequencing is the most effective genetic test, it may not be available in some parts of the world. Clinical geneticists may use other genetic tests, such as Sanger sequencing. Sanger sequencing uses a computer to look for gene mutations in a person’s DNA. If an individual has a classic CdLS phenotype, Sanger sequencing of the NIPBL gene is the preferred initial test. If an individual has a non-classic CdLS phenotype, other genes associated with the CdLS spectrum can be sequenced (R9).

Testing for Mosaicism

When a change in a gene associated with CdLS cannot be found using panel or Sanger sequencing, genetic testing can evaluate an individual’s DNA for mosaicism. Mosaicism is where there are different populations of cells which have a different genetic make-up in a single person. See the Mosaicism section.

Multiplex Ligation-dependent Probe Amplification

If genetic testing is not able to find mosaicism in an individual’s DNA, a test called multiplex ligation-dependent probe amplification (MLPA) can be considered. MLPA looks for deletions or duplications in the NIPBL gene.

Molecular diagnostic pathways for cornelia de Lange syndrome.

NGS = next generation sequencing/modern genetic testing approaches.

Fig. 5: Diagnostic pathways for Cornelia de Lange (CdLS) Syndrome. In individuals with the classic phenotype, the first-line approach should be modern genetic testing approaches by either examining multiple genes at once, examining all of the genes that code for proteins in an individual or by examining the complete DNA of an individual. This should include all of the currently known CdLS genes (NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11). If these approaches are not available, genetic testing should begin by examining NIPBL (classic CdLS phenotype). In individuals with the non-classic CdLS phenotype, the phenotype itself may allow experienced clinicians to determine which gene should be sequenced first; if this cannot be determined, modern genetic testing approaches can be performed. In the case of negative results, NIPBL and the other CdLS genes should be tested for mosaicism using tissues other than blood (as not all of the cells tested may show the mutation), for example, cells in connective tissues, cheek/mouth swabs or cells from urine. There are other tests that can be carried out to investigate the NIPBL gene (i.e. whether it has been deleted or duplicated), these are called multiplex ligation-dependent probe amplification or chromosome microarray. These tests can be used before other genetic testing approaches, or may be used following these approaches to investigate gene variants further.

summary section

Diagnosis recommendations:

R7: If a prenatal ultrasound scan (sonography) detects features consistent with CdLS, possibilities for prenatal genetic testing should be discussed with the parents.


R8: If a causative gene change has been detected in an earlier child or pregnancy, reliable prenatal diagnostic testing should be discussed with the family. Targeted variant testing can be performed using DNA derived from the placenta or amniotic fluid.


R9: If available, first-line genetic testing should be performed using panel sequencing to screen all genes known to cause CdLS spectrum (NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11). Medico-legal, technical, and insurance-related national practices may require other tests, such as Sanger sequencing of individual genes.

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