An Answer and a New Beginning:

The Cornelia de Lange Syndrome
Gene is Identified

Archive 2004

In May of 2004, Research teams led by Dr. Ian Krantz at The Children’s Hospital of Philadelphia (CHOP) and Prof. Tom Strachan at the Institute of Human Genetics, University of Newcastle, reported in Nature Genetics that they have identified a gene on chromosome 5 that causes Cornelia de Lange Syndrome (CdLS).

News of this discovery has touched people with CdLS and those who care for them in many ways. This discovery is still so new that there are many questions that cannot be answered at this time. As the research continues and additional information is learned about this gene, the CdLS Foundation will continue to update our publications and website at www.cdlsusa.org. If you have questions about this discovery, please contact us at 1-800-753-2357.

• To confirm the diagnosis
• To understand the diagnosis of CdLS, improve existing therapies, and design new medical therapies
• To understand the role the gene plays in development
• To offer reassurance, through genetic testing, that other family members are not affected
• To provide accurate information and counseling resources for future pregnancies
• To generate broad interest about the syndrome in the medical/scientific research community

In the following section Dr. Ian Krantz answers many anticipated questions. We ask for your patience as we learn more about this discovery and how we can better serve you and all individuals with CdLS.

Will all people who have the diagnosis of CdLS have this gene?

All people have two copies of this gene. CdLS occurs when one of those copies has a change, or mutation, that causes it not to function properly. Currently, we are able to find a change in this gene in approximately 50% of individuals with CdLS. A higher percentage may be identifiable as testing procedures become more sophisticated.

How do you know that this gene identification is correct?

Changes (called mutations) have been found in many individuals with CdLS that are not present in their parents, meaning that a new change developed in those individuals resulting in CdLS. In a few rare families who have more than one child with CdLS, each of the children with CdLS has had the same mutation, which has not been found in any unaffected family members. We are able to tell by the type of change in the gene how it will affect the protein for which it codes; in all cases the changes result in a very abnormal protein or in a protein that is not made. A second research group in the United Kingdom has also confirmed these findings.

Is it important to confirm the diagnosis of CdLS?

The diagnosis of CdLS is still primarily a clinical diagnosis based on observable signs and symptoms. A change in the gene may help to clarify some questionable diagnoses, however we must remember that as of now we have not found a change in this gene in all of our research participants who have a diagnosis of CdLS. This leads us to believe that a person with CdLS could have a change in this gene, or possibly a different gene, that we cannot find at this time.

Is there a test for CdLS available now?

Now that the gene has been found there is much more work to be done. At present, the lab at CHOP is working around the clock with the blood samples that have been given to Drs. Laird Jackson, Ian Krantz, and Antonie Kline by families with the hope that this day would arrive. We are happy to accept new samples from individuals and families with CdLS. Please contact the CdLS Foundation for more information at 1-800-753-2357 or info@cdlsusa.org.

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. We use the analogy of reading a very long book (e.g. War and Peace) and looking for a single typographical error. You may read the whole book and miss the “typo,” however when you do find it then it is easy to test other family members (i.e. you know that the change is on page 875 in the second paragraph). 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 since we 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 however 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.

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% at this time.

If I previously donated blood will I be contacted and told the findings?

In order to participate in testing through Dr. Krantz’s lab you will need to sign a consent form as testing is presently being offered on a research basis only. As part of the consent form you must indicate whether or not you want to know the results of the study. If you consent to know the results, they will be reported back to you. Since the study is a research study and not being performed in a clinical lab, it is mandated that any changes identified must be reconfirmed on a second sample before they can be reported. Unfortunately, this means that a second blood sample is needed from the individual with CdLS to confirm the finding. This is an important step for quality assurance and for reporting such critical information back to a family.

What are the long-term implications of this discovery?

Now that the basic cause of CdLS has been discovered we can begin to understand how this change results in the clinical differences seen in affected individuals. By studying how this occurs we will be able to understand the clinical problems that individuals with CdLS face on a very basic level. With time, we hope this will result in better care for affected individuals. It is anticipated that identification of the CdLS gene will also interest other researchers to get involved in studying CdLS, which can only help speed progress in caring for individuals with CdLS!