Genes of Interest on Distal 18q
Here, we will talk about genes on distal 18q that have been linked to specific health concerns. It is important to have an understanding of basic genetic concepts. You can read about genes and chromosomes here.
At this point, we only know of a few genes on distal 18q that we know have an effect when one copy is missing. In other words, we cannot link most of the genes on distal 18q with specific health or developmental concern. As we learn more about the genes on chromosome 18, we will be able to make better predictions about what to expect based on a person’s specific deletion.
Families and physicians are able to keep track of the latest information about the genes on chromosome 18 through the Gene Dosage map.
Below, we have included information about significant genes on distal 18q that we know are associated with significant health concerns when deleted.
SMAD4: Juvenile Polyposis and Hereditary Hemorrhagic Telangiectasia
We know that people who have mutations in this gene are at risk for two genetic conditions: juvenile polyposis and hereditary hemorrhagic telangiectasia. Juvenile polyposis is a condition that predisposes individuals to developing a certain type of polyp in the gastrointestinal tract. There is an increased risk for cancer associated with these polyps. Hereditary hemorrhagic telangiectasia is a condition that leads to malformations in the way blood vessels are formed. This can cause bleeds in various places of the body, including nosebleeds, the gastrointestinal tract, the brain, the liver, or the lungs.
At this point in time, we don’t know precisely what this means for people with distal 18q-. The mutations that have been linked to these conditions are different from the full gene deletions found in people with 18q-. In addition, no individuals within the research study at the Chromosome 18 Clinical Research Center have been diagnosed with these conditions, though none have undergone endoscopies to rule them out, either. That being said, there is one person reported in the literature that has a deletion of 18q as well as JPS. It is reasonable to conclude that there is at least some increased risk for JPS, though the magnitude of that risk is uncertain.
TCF4: Pitt Hopkins Syndrome
This gene has been linked to a condition first described in 1978 called Pitt-Hopkins syndrome. It is located in chromosome band 18q21.2. If a person with distal 18q- has a deletion that includes
TCF4, that person is likely to have features of Pitt-Hopkins syndrome as well as the other
features of distal 18q-, which are described in detail below.
The features of Pitt-Hopkins include developmental delays, cognitive impairment, breathing abnormalities, and seizures.
TSHZ1: Aural Atresia and Stenosis
This gene is associated with one of the most common features of distal 18q-: aural atresia and stenosis (narrow or closed ear canals). It is located in chromosome band 18q22.3. About 80% of people with deletions that include TSHZ1 have narrow or absent ear canals.
Genes Under Investigation
We have talked about genes that we know to be linked to features of 18q-. However, there are many more genes that we are still working to understand. The genes discussed below are known as candidate genes. These are genes that we believe may play a role in the features of distal 18q-, but additional evidence and research will be necessary to confirm that suspicion.
TXNL1 (54,270,053-54,306,270). There has been a suggestion that deletions of this gene can lead to an increased risk of autism and/or learning disabilities. In addition, a small number of individuals with deletions of this gene have had other features, such as birth defects and seizures. However, we are still working to understand whether it is this gene that is responsible for the findings. More work remains to be done to truly understand what a TXNL1 deletion actually means.
NETO1 (70,409,549-70,534,810). Mice that are missing this gene seem to have difficulty with certain cognitive functions. For example, they have difficulties learning to adapt to changes in their environment. They have trouble with remembering information about their environment and where they are within that environment. However, deletions of this gene have also been found in people that have no medical or developmental concerns. So, we still have much to learn about this gene, and what it means for people with 18q-.
CYB5A (71,920,527-71,959,251). People who have a mutation in both copies of this gene develop a specific condition called 17,20 lyase deficiency, which leads to changes in the development of male genitalia. We do not know whether or not one missing copy of the gene, as is the case in some individuals with distal 18q-, is enough to cause genital anomalies. We know that males with 18q- frequently have genital changes, such as cryptorchidism, hypospadias, and micropenis. In addition, no male that has a deletion of this genes has fathered children. However, most males with a deletion of this gene have not undergone a fertility evaluation. Additional research will be required to determine what role, if any, CYB5A plays in male fertility.
MBP (74690789-74844774). There had been a great deal of interest in this gene because it is a candidate gene for dysmyelination, a well-known feature of distal 18q-. In addition, deletions of MBP may be linked with the type of sensorineural hearing loss frequently seen in individuals with distal 18q-. We are still working to understand what role, if any, this gene plays in the features of distal 18q-.
NFATC1 (77,160,326-77,289,323). Mice who are missing this particular gene seem to have some immune changes. We know that people with 18q- have a higher incidence of autoimmune conditions, so this is a particularly interesting finding. However, there is also some evidence that missing one of these genes might protect someone from autoimmune conditions. Therefore, the relationship between this gene and immune function is unclear. In addition, there are some reports that people who are missing this gene may be at a higher risk for degenerative lumbar scoliosis. Indeed, people with distal 18q- are at an increased risk for scoliosis. Again, additional research is necessary to determine the role that NFATC1 plays in distal 18q-.