3.2 Chromosome changes that include TCF4

3.2 Chromosome changes that include TCF4

Sometimes, a long stretch of a chromosome is gone. This is called a 'deletion'. When the bit is at the end of a chromosome, this is called a 'terminal' deletion. And when the missing bit is somewhere in the middle of the chromosome, this is called an 'interstitial' deletion. These bits can be of different lengths, and the effect of such a deletion depends on the genes that were encoded in the missing bit. In people with Pitt-Hopkins syndrome, scientists have found deletions of certain lengths (ranging between 1.2 and 12 million base pairs) that include a the part of the long arm of chromosome 18 (18q) that coded for TCF4. These people look and behave exactly like people who only have mistakes within the part of the DNA that codes for TCF4.^2,3,14,16-22 As long as the missing bits are within the mentioned range, it doesn't make any difference how large the bit is that has been lost, or how many other genes were coded by that bit: the effect is still that people look and behave and develop like people with Pitt-Hopkins syndrome.^18,23 Therefore, people with such deletions should also be diagnosed as having Pitt-Hopkins. (Figure 2B). 

Sometimes the missing bits from the long arm of chromosome 18 are larger (up to 25 million base pairs) or the missing bit comes from the end of the chromosome (terminal deletion). Scientists have reported about individuals with such changes in the dna, who don't exactly look and behave like people with Pitt-Hopkins, but only share some characteristics of Pitt-Hopkins syndrome.^22,23 These large deletions should be considered 'contiguous gene syndromes', which means 'syndromes caused by changes in genes lying next to each other on a chromosome. Not just the missing bit encoding for TCF4, but also other genes might contribute to the way people look and behave. When describing an individual with these DNA changes, it is better to say they have “18q deletion syndrome”, adding the exact breakpoints on the long arm of chromosome
18 (Figure 2B). 

In other cases, people only have such large deletions of this part of chromosome 18 in some of the cells in their body. When a person has a change in a part of their cells, but not in all, this is called a 'mosaic', just like when a mosaic of tiles is made that has parts of one color of tile and parts of another color. When such a mosaic-like change in the long end of chromosome 18 causes a set of symptoms, this should also be called a "18q deletion syndrome" ,^18,21,24. Another possibility is that deletions happen at both ends of a chromomsome, after which the remaining ends stick together and form a ring ('ring chromosome').²⁵ Again, if this happens with a large part of the long arm of chromosome 18q, the result should be called a 18q deletion syndrome.

Scientists have described individuals with other changes in the long arm of chromosome 18q, such as 'balanced translocations'. This is when a part of a chromosome has broken off and gotten attached to another chromosome, which in turn has a bit broken off that has attached to the first chromosome. These people don't actually miss any dna, it's just in another location. Sometimes the break happens in such a way that the part coding for TCF4 can't function normally.^2,26–29 The way individuals look and behave varies, and the diagnosis of PTHS should only be accepted if the the clinical criteria are fulfilled).