» Genetics

Gene search special

With the discovery of the gene there are lots of questions that families are asking. Professor Tom Strachan, who led the Newcastle research team and Dr Ian Kranz, from Philadelphia Children’s Hospital answer the most common questions.

How does a change in the NIPBL gene 
Emma Tonkin of the University of Newcastle breaks the news to families at Stratford.

cause CdLS?

The NIPBL gene normally makes a protein that is particularly important in controlling how we develop in the womb and in early life.

People normally have two active copies of this gene, one inherited from their mother and one from their father. Both gene copies are needed because the amount of the protein that they make between them is critically important – if only one gene copy were to be present, the amount of protein made would only be half of that which is normally made, and the reduction in protein can, by itself, cause major problems during development.

CdLS occurs when one of the two NIPBL gene copies has a change, or mutation, that damages the gene so that it no longer works properly – either the damaged gene copy fails to make any protein or it makes a faulty protein. So, although one of the two gene copies is unaffected and continues to make the right protein, the damage to the other gene copy is enough to cause CdLS.

Will all people with CdLS have a defect in this particular gene?

Currently, we are able to find a change in this gene in 50-60 per cent of individuals with CdLS.

As testing procedures are extended and refined, we expect to find a change in a much higher percentage of CdLS individuals. However, there is a possibility that a second, as yet unknown, gene is involved in some CdLS individuals.

We will know the answer to this question when we have had the opportunity to test a larger number of CdLS individuals.

How do you know that this gene identification is correct?

Changes (called mutations) that can be expected to damage this gene have been found in many individuals with CdLS but are absent in their parents, meaning that a new change has developed in those individuals, resulting in CdLS.

When unrelated individuals with CdLS test positive for changes in the NIPBL gene, the changes are typically different from each other. However, in each case the change is one that could be expected to cause the gene to stop making any protein, or to make a faulty version of the normal protein.

Is it important to confirm the diagnosis of CdLS?

The diagnosis of CdLS is still primarily a clinical diagnosis and is determined by careful examination of observable signs and symptoms. However, sometimes other disorders show some of the same features and so it can sometimes be difficult to be sure that the correct diagnosis has been made.

A damaging change in the NIPBL gene will confirm the diagnosis of CdLS. However, at this time a failure to find such a change does not mean that the individual does not have CdLS. Instead it could simply mean that the testing system is not advanced enough, or it could mean that a second, as yet unknown, gene can be involved in some CdLS individuals.

Is there a test for CdLS available now?

It is best to think in terms of doing a range of different tests to find changes in the NIPBL gene. We’ve started off doing many different tests and running them all one after another. We can detect damaging gene changes in about 50 per cent of CdLS individuals. So right now we have a testing system that is only effective half of the time, and as the gene is very large it takes a lot of effort.

We need to expand the number of tests, however, to see if we can reach a detection rate closer to 100 per cent, and this will take some time.

Can my child be tested? Can I be tested? Can my family members be tested?

The first person to be tested in any family would be the individual with CdLS. Testing for changes (mutations) in the CdLS gene is complicated by the fact that it is a very large gene.

As an analogy, imagine the following. You are a bookseller and have received a new edition of a very long book (e.g.Lord of the Rings) and you have been told that a certain number of the books have the same single typographical error. You may read the whole book and miss the “typo,” however when you do find it, e.g. on page 610, second paragraph, third line, then it is easy to check which of the other books has the same change. So once a change is identified in the individual with CdLS, testing for other family members, or even prenatal testing, is relatively easy and fast because they should have the same change and we would know exactly where to look.

What does a positive test mean for my child, our family?

A positive test will confirm a diagnosis of CdLS; but at the moment not finding a change does not rule out the diagnosis.

Once a change has been identified in an affected individual then it allows for easy testing of other family members who may choose to be tested, and permits the possibility of prenatal diagnosis.

What does a negative test mean for my child, our family?

In some cases where the diagnosis is doubtful it may contribute additional evidence against the diagnosis, however we know that even in individuals with classic features of CdLS we are only able to identify mutations in approximately 50 per cent of cases at this time.

Are there any other labs willing to accept samples for testing?

The American group led by Dr. Ian Krantz has reported in a paper in Nature Genetics that they can detect mutations in 20 per cent of cases and it is possible that they too may be willing to accept samples for testing.

The majority of the samples tested in our Newcastle lab are from European individuals with CdLS and we expect that the majority of the samples being tested in Dr. Krantz’s lab are American. Several diagnostic labs have expressed an interest in developing this test which may be available soon.

What are the long-term implications of this discovery?

Now that the basic cause of CdLS has been discovered we will be able to carry out DNA tests to verify diagnosis or establish whether or not a fetus at risk of Cornelia de Lange syndrome has a harmful change in the NIPBL gene. We can also begin to understand how this change results in the clinical differences seen in affected individuals. In the longer term we hope to fully understand how damages in the gene cause the disorder and how the normal gene functions. When we have that information we may be able to devise some forms of intervention that may reduce the severity of the disorder in the womb or the incidence of the disease e.g. by oral administration of some supplement to the mother (in much the same way as oral supplements of folic acid have been found to reduce the chance of having a child with spina bifida).

If I have a specific question about the tests or the research, how can I contact the research doctors at Newcastle?

There is now a specific email address that families or professionals can use for specific CdLS queries. It is ncdls@ncl.ac.uk