Ring 18 is an ultra-rare condition occurring in approximately 1 in 300,000 live births. However, among the ring chromosomes it is one of the most common. This is probably because chromosome 18 is very small and has very few genes even given its short length thereby making Ring 18 a survivable condition.
The ring chromosome, by definition, has a loss of genetic material from both ends of the normally linear chromosome. In order for the two chromosome arms to anneal together, the caps at the ends of the arms must be lost, often along with some valuable genetic material. How exactly that happens, and the factors that prompt such an action are not known.
Most of the people with Ring 18 have one normal copy of chromosome 18, with the second copy of chromosome 18 being replaced by the ring chromosome. However, ring chromosomes are unique in comparison to the other chromosome 18 conditions because about 41% of the people with Ring 18 have some form of mosaicism.
Mosaicism means that some of the cells of someone’s body have one genetic makeup, while other cells have a different genetic make-up. About 14% of those with Ring 18 have some cells with a normal 18, plus the ring 18 chromosome, while other cells only have a ring 18 chromosome and no normal copy of chromosome 18. Another 12% of people with Ring 18 have some cells with a normal 18 plus the ring 18 chromosome, while other cells have the ring 18 chromosome along with a chromosome 18 with a deletion. The other 14% of people with Ring 18 have some other combination including cells with double rings, or some with a few normal cells. All in all, ring chromosomes are very dynamic entities and generate a huge amount of diversity within the different cells, tissues, and organs of any one person’s body.
The only way to determine the type and level of mosaicism is to use “old fashioned” microscopic analysis (karyotype) to visualize the chromosomes and determine their shape. The limitation is that these results are only applicable to the samples being examined. The level and type of mosaicism could be different in a different tissue. Molecular techniques such as microarrays, although much, much higher resolution, only determine the net number of copies for very small sections at thousands of different positions along each chromosome, averaged across the blood or tissue sample being evaluated. This technique cannot tell you the shape of the chromosome, and sometimes will not detect low levels of mosaicism.
And as if that is not an overwhelming about of variation between different people with Ring 18, there is more! The actual molecular content of the ring chromosome is unique to every person with Ring 18. In particular, about 1/4 of individuals have a ring chromosome with a deletion that includes the entire short (p) arm. However, each one of those individuals has a unique sized deletion from the end of the long (q) arm of chromosome 18. The other 3/4 of people with Ring 18 have unique deletions from both the q and p arms of the ring chromosome. This individual variation from person to person defies any group uniformity, making it impossible for an individual with the diagnosis of Ring 18 to know what is applicable to them or not from a listing of all possible symptoms for the entire group. The rare individuals who have a p deletion and almost no q deletion will find the 18p- information most appropriate. Alternatively, those few people with a small p deletion and more significant q deletion will find the 18q- information more useful. But the majority of those with Ring 18 will benefit from the combination of information from both 18p- and 18q-.
Fortunately, thanks to the work of the Chromosome 18 Clinical Research Center, the identification of the genes causative of specific consequences of a deletion and the identification of specific small chromosome regions associated with a particular issue, can help an individual person to determine which information is most relevant to them. This information is evolving and progressing as more research continues.
Cody, JD. Ring Chromosome 18 In: Human Ring Chromosomes; A Practical Guide for Clinicians and Families. Li P and Liehr T (eds.) Springer Nature Switzerland AG, 2024. Pages 261-270
