3.4 TCF4 variants and non-PTHS phenotype (§1: 3.4 TCF4 variants and non-PTHS phenotype)

3.4 TCF4 variants and non-PTHS phenotype

'Phenotype' is a word used by scientists to describe the combination of characteristics or traits of a person: the way they look, the way they develop, the way they move and behave. The 'clinical diagnostic criteria' (see section 2) describe parts of a person's phenotype. The word 'genotype' is used to talk about a person's DNA. As written above, most people who have the characteristics of Pitt Hopkins syndrome have a change in the DNA concerning the gene for the protein called 'Transcription Factor 4'. But not all the changes that have been found in the part of the DNA coding for transcription factor 4 lead to Pitt Hopkins syndrome. 

In some cases, the only problem that seems associated with such changes is mild problems with thinking (mild intellectual disability), in other cases, the intellectual disability is worse and these people also have a few of the Pitt Hopkins characteristics. ^{22,26,29,33-37} However, if a person does not look and act as described in the 'clinical diagnostic criteria' (see section 2), they should not get the diagnosis Pitt Hopkins just because they have a mutation in the DNA coding for TCF4 (R3).

We don't completely understand why some TCF4 variants lead to milder differences in behavior and thinking ability. Changes in particular parts of the gene (exons 9 to 19, to be precise) almost always lead to Pitt Hopkins, but people with changes in exons 1 to 4 have mild intellectual disability and people with changes in exons 7 to 8 have worse thinking problems and also sometimes some of the characteristics of Pitt Hopkins - but not enough to actually be diagnosed with Pitt Hopkins syndrome33 (Figure 2B).   

The best explanation that we have so far, is that when the part of the recipe for TCF4 that is described in exon 9 to 19 is wrong, then the TCF-4 protein that is made based on this faulty code never works. But when the changes in the recipe for TCF-4 are in another location (for instance exon 1 to 4 or exon 7 to 8), some of the TCF-4 proteins that get made based on these DNA mutations work after all. This can explain why people with such DNA changes experience fewer problems. ³³