Our entire body is composed of very many cells. Each cell has its own function. Groups of cells form together the various parts and organs of our body. Each cell has an outside (cell membrane), an inner mass (cytoplasma) and a core (nucleus).

In every single cell there are many different proteins to perform all functions of the cell. All proteins are formed from the DNA that is present in the nucleus. So the DNA can be seen as the ‘cookbook’ for the proteins of the cell.

The DNA is present in the nucleus in nice small packages, to facilitate the reading of the DNA. Each package is called chromosome. All DNA together is divided into 23 different chromosomes, of which you have each time two (a pair). So in total in the human cells there are 46 chromosomes.

From every pair of chromosomes you have inherited one from your father and one from your mother. So everyone has inherited 23 chromosomes from father and 23 from mother, each time one of each pair. This combination is established at the moment of the fertilization.

How did this happen?

PTHS in Alexandra was caused by haploinsufficiency of TCF4 resulting from a 4.2 Mb micro-deletion of the chromosome region in which TCF4 is located (18q21.2). Most affected individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant or deletion.

Put simply, this error occurred prior to conception in either the sperm or the egg and was completely by chance. It could have happened to anyone, it was nothing we did or didn’t do.

We have given the chromosomes a number, mainly based on the size of the chromosomes. Chromosome 1 is the largest chromosome, chromosome 2 is a bit smaller, etc, until chromosome 22 which is the smallest one. The last number is not named 23 but either X or Y; the reason for this is that they determine whether a person is a male or a female. Someone with two X chromosomes is a female, someone with one X and one Y chromosome is a male. You can’t have just two Y chromosomes: that is not viable, as there is too much important information present in the DNA of the X chromosome.

Each chromosome consists of many genes. A gene is the information that codes for a protein, and is fixed at a specific spot on the chromosome. Examples of a gene are the gene we have for the protein insulin, or the genes you have for your blood type or genes that determine what color eyes you have.

There are many variations possible in the DNA. This ensures that no two people are alike. Such changes do not give rise to disorders. Other changes in the DNA are not tolerated well by the body and cause problems. Such a change is called mutation. Such a change manifests itself as a birth defect such as a congenital heart anomaly or a syndrome, and sometimes they manifest as diseases later in life like Alzheimer dementia.

In children with Pitt Hopkins syndrome a change in the TCF4 gene on chromosome 18 can be present. TCF4 is an important gene because it codes for the protein TCF4. We know that this protein is very important for the development of the brain. We do not know yet all functions of TCF4.


Raoul CM Hennekam MD PhD, Professor of Paediatrics and Translational Genetics, University of Amsterdam, The Netherlands, Summer 2010.

Source: Pitt Hopkins Research Foundation