18p- Genes Under Investigation
We have talked about genes that we know to be linked to features of 18p-. 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 18p-, but additional evidence and research will be necessary to confirm that suspicion.
CETN1 (580,369-581,524): Some research has suggested that male mice that have changes in this gene are infertile. We know that some women with 18p- have had children. At this point, we are not aware of any men with 18p- that have had children. We do not know whether this is because they are not able to have children or because they simply have not yet tried to have children. Additional time and data will be necessary to determine the effects of a CETN1 deletion.
LAMA1 (6,941,743-7,117,813): This gene is interesting because research has linked it to several different findings. For example, mice that carry a change in this gene have abnormalities in the blood vessels of the retina (the back of the eye that is responsible for gathering light and transmitting images to the brain). Another study suggested that this gene is linked to specific skin abnormalities. The Chromosome 18 Clinical Research Center continues to collect data with the aim of understanding the role of LAMA1 in the features of 18p-.
TWSG1 (9,334,765-9,402,418): Mice that have changes in this gene seem to have an increased risk for various congenital anomalies, particularly if they were exposed prenatally to a specific chemical. In humans, the link between this gene and congenital anomalies is less clear. More research is necessary to clarify the relationship between TWSG1 and birth defects.
AFG3L2 (12,328,943-12,377,275): Point mutations in this gene have been linked to a condition called spinocerebellar ataxia, type 28 (SCA28). Point mutations are changes in one or a few base pairs within the gene. SCA28 causes a progressive ataxia, which is a lack of muscle coordination. Other features can include speech difficulties, increased reflexes, and some ocular abnormalities, such as nystagmus (involuntary movements of the eye) and ptosis (drooping eyelids). Symptoms typically appear during adulthood. A point mutation, however, is different than the genetic change in 18p-. We don’t know if people with a deletion of the entire gene are at risk to develop SCA28. There has been one case report in the literature of someone with a microdeletion of 18p with ataxia; however, this person had several other chromosome changes as well. The Chromosome 18 Clinical Research Center has evaluated several adults with 18p-, none of whom had features of SCA28. It may be that deletions of AFG3L2 do not cause SCA28 in all individuals with 18p-. It may also be that some of the study group may develop signs of SCA28 as they get older. The Research Center will continue to collect data with the goal of understanding the effects of an AFG3L2 deletion.
PTPN2 (12,792,301-12,884,334): Some studies have linked PTPN2 to inflammatory bowel disease and rheumatoid arthritis. Although inflammatory bowel disease is not a recognized feature of 18p-, rheumatoid arthritis has long been associated with 18p-. Other autoimmune conditions have also been linked with 18p-, such as lupus and psoriasis. It is possible that this gene plays a role in autoimmune conditions in 18p-.
As discussed here, there seems to be an increased risk for autism in people with 18p-. There have been several genes on 18p that may be associated with autism. These include DLGAP1 (3,499,183-3,880,068), LCCR30 (7,231,137-7,232,042), ANKRD12 (9,136,751-9,285,983), and IMPA2 (11,981,427-12,030,885). The genetics of autism are complex, and we still do not fully understand how and if deletions of these genes lead to autism in people with 18p-.