Distal 18q deletion syndrome - TCF4 and TSHZ1 genes, and Chromosome 18

Distal 18q deletion syndrome, also known as 18q syndrome or Grouchy syndrome, is a chromosomal disorder due to the absence of a part of the long arm of chromosome 18. The term "distal" means that the part that has been lost was near one end of the chromosome.

This condition may result in a wide variety of signs and symptoms, including short stature; hypotonia; hearing loss, due to auditory stenosis or auditory atresia; foot abnormalities, such as clubfoot or rounded feet; disturbances of eye movement and other vision problems; cleft palate; hypothyroidism; congenital heart defects; renal problems; genital abnormalities; and skin disorders. Some affected people have microcephaly and slight facial differences, such as sunken eyes, hypoplasia of the facial middle third, a wide mouth and prominent ears.

Distal 18q deletion syndrome can also affect the nervous system. A frequent neurological feature is demyelination. Frequently, in affected people the production of myelin takes place more slowly, and they may not even have normal amounts of myelin in adulthood. Most of these people manifest neurological problems, although it is not clear to what extent these problems are related to demyelination. These disorders can vary from mild to severe, and include developmental delay, intellectual disabilities and learning difficulties. In addition, affected individuals may suffer from seizures, hyperactivity, and mood disorders such as anxiety, irritability and depression, as well as autism spectrum disorders.

This process is due to a deletion of genetic material in a copy of chromosome 18, and can be located in any position between the region 18q21 and the end of the chromosome. The size of the deletion varies among affected individuals. It is believed that the signs and symptoms of distal 18q deletion syndrome are related to the loss of multiple genes from this part of chromosome 18, some of which have not been identified. Some of the affected genes are the TCF4 gene (transcription factor 4) and the TSHZ1 gene (teashirt zinc finger homeobox 1).

The TCF4 gene, located on the long arm of chromosome 18 (18q21.2), encodes a protein that interacts with other proteins and binds to specific regions of DNA to help control the activity of many genes, acting as a transcription factor. The TCF4 protein is part of a group of proteins known as E proteins. Each of the E proteins binds to another identical or similar protein, and subsequently binds to a specific DNA sequence known as E-box. E proteins are involved in many aspects of development, and the TCF4 protein plays a role in cell differentiation and apoptosis. The TCF4 protein is found in the brain, muscles, lungs and heart, and also appears to be expressed in various tissues before birth. Affected individuals whose deletions include the TCF4 gene generally have signs and symptoms of Pitt-Hopkins syndrome, in addition to other features of the distal 18q deletion syndrome that are probably associated with the loss of nearby genes.

The TSHZ1 gene, located on the long arm of chromosome 18 (18q22.3), encodes a colon cancer antigen that was defined by serological analysis of recombinant cDNA expression libraries. This encoded protein is a member of the C2H2 type zinc protein family, and may be involved in the transcriptional regulation of developmental processes.

Distal 18q deletion syndrome is considered to be an autosomal dominant inheritance process, which means that a copy of the region removed on chromosome 18 in each cell is sufficient to give rise to the characteristics of the disease. Most cases are due to a new deletion that occurs more frequently during the formation of reproductive cells or at the beginning of embryonic development, so that affected people generally have no history of the disease in their family. In some cases, distal 18q deletion syndrome can be inherited, usually from an affected parent with relatively mild signs and symptoms. The disease can also be inherited from an unaffected parent who is a carrier of a balanced translocation, in which genetic material is not gained or lost. Individuals with a balanced translocation do not usually manifest related health problems; however, translocation can be unbalanced as it is transmitted to the next generation. Children who inherit an unbalanced translocation may have a chromosomal rearrangement with extra or missing genetic material. The inheritance of an unbalanced translocation that results in the deletion of genetic material from the distal region of the long arm of chromosome 18 would cause distal 18q deletion syndrome.

Tests performed in IVAMI: in IVAMI we perform the detection of deletions in chromosome 18 associated with distal 18q deletion syndrome, by means of the PCR quantification at real time.

Recommended samples non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).