Genetic tests to confirm a diagnosis of Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome is caused by a change in a specific gene, and that is why someone who has received a clinical diagnosis   should be offered genetic testing. 

We know of one gene, TCF4, that causes Pitt-Hopkins syndrome. This gene is responsible for many important developments, for example the formation of the brain before birth, the formation of the tissues of the face, the way nerves function, and how the body fights infections.

Sometimes the gene is missing or partially missing (this is known as microdeletion). This can either affect the TCF4 gene alone, or other genes nearby on chromosome 18 as well. A child or adult found to have the TCF4 gene missing is said to have ‘18q microdeletion syndrome’. If this is the case someone may show the features of Pitt-Hopkins, and other unusual signs and symptoms as well.

Some children with a change in the TCF4 gene may be delayed in their development but they do not have PTHS. For example, they do not have the characteristic facial features or breathing problems. Such children or adults should not be diagnosed with Pitt-Hopkins syndrome. A doctor should use the points system  in these guidelines to diagnose or rule out PTHS.

Pitt-Hopkins is a genetic condition. Most cases are caused by a change in the TCF4 gene that has happened for the first time in that individual. This is known as a ‘de novo’ case, which means ‘new’. 

In rare cases a parent may carry the gene change that causes Pitt-Hopkins Syndrome  in a proportion of the cells in their body but not show signs themselves. The parent is referred to as having ‘mosaic’ PTHS.

What are the chances of someone being born with Pitt-Hopkins syndrome?

* If two parents have a child with Pitt-Hopkins syndrome, the chances of them having another child with the same syndrome is only 2% (The group who created these guidelines had details of 273 people with PTHS. In five of these families there were two children with PTHS, and on this basis the group calculated the 2% figure.) This small risk is present because of the chance that one of the parents may be have the  mosaic form.

* A healthy brother or sister of someone with Pitt-Hopkins has no greater risk of having a child with the syndrome than anyone in the general population

* If someone with PTHS had a child, there would be a 50% (one in two) chance of the baby being born with the syndrome as well. This is because they already have the altered gene that causes the syndrome and there is a 50% (one in two) chance of any child of theirs inheriting it.

How are genetic tests carried out?

Nowadays there are many ways of performing genetic (DNA) tests. A technique that is often used is called ‘next generation sequencing’. This means either all of an individual’s genes, or a selected group of genes can be checked for changes. 

Sometimes a change in the TCF4 gene is found in a child who does not show the signs and symptoms of Pitt-Hopkins syndrome. 

In such a case it could be either that the particular TCF4 gene change involved is not causing any problems or that the child has a variant in another part of the TCF4 gene, which is causing problems in his or her development, but not PTHS.  

In this case it can be very difficult to determine whether the change in the gene will cause any harm or not. Doctors need to evaluate the child very carefully, and make all the following checks:

* Is there is anyone in the family with PTHS or a similar syndrome?

* Has this particular change in TCF4 been seen and reported before?

* If it has been reported before, was it in a healthy person or someone with PTHS or another disorder?

* Where exactly in the gene is the change is located, and what type of change is it? The answers to these can make a significant difference. There are international criteria available for this.

All together this means the doctor needs time and experience to check all the above, before deciding whether or not a change in the TCF4 gene is harmful or not. 


3/ Changes in the gene TCF4 can cause PTHS but can also cause other syndromes that are linked to cognitive problems. The latter group of children and adults should not be labelled as having PTHS.

4/ If a family has a child with PTHS and the diagnosis is confirmed by DNA studies, the statistical chance that the same couple will have another child with PTHS is around 2%.

5/ If a change in the TCF4 gene is found through DNA testing, it is not always easy to determine whether it is doing any harm or not. Especially if the characteristics do not resemble PTHS very much. Several checks need to be carried out: carefully checking the child; checking whether the same or similar syndrome occurs in the family; whether this particular genetic change has been seen in anyone before; what the type of change is and precisely where within the gene it has occurred. 

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