Probably everyone living with 22q13 deletion syndrome knows that it is much more than a disease of the brain. My son, David, is not unusual in that regard. He has flaky toenails, GI problems, and poor temperature regulation. 22q13 deletions affect the entire body. I worry that he will someday get cancer (see my earlier post “Can 22q13 deletion syndrome cause cancer?”) and I worry about painful conditions that he is unable to express to me (see “Can 22q13 deletion syndrome cause ulcerative colitis?“). That said, as parents, we see our child’s future stunted by intellectual disability: the loss of typical cognitive development. What causes this defining feature of 22q13 deletion syndrome?
Somewhere around 95% of individuals with 22q13 deletion syndrome have terminal deletions, where the chromosome has a piece broken off the end. About 10% of the deletions are inherited (unbalanced translocation), but the rest are not (de novo). (The remaining individuals have interstitial deletions: the broken and missing material is somewhere inside the chromosome without affecting the end of the chromosome.) 22q13 deletion syndrome did not originally include microdeletions or mutations of a single gene. Some microdeletions or mutations are included under the umbrella name “Phelan-McDermid syndrome,” although other cases of mutations and microdeletions are sometimes included and sometimes not: it depends on who you ask. Because the term “Phelan-McDermid syndrome” is used so inconsistently, I avoid using it (see “22q13 deletion syndrome – an introduction”). There is another reason to omit discussing single gene mutations and microdeletions when discussing a contiguous chromosomal deletion syndrome like 22q13 deletion syndrome. Single gene mutations can have very funny and unpredictable effects. A mutation can have no effect, can be just like the loss of a gene, or it can have a “dominant negative” effect. A dominant negative means that the gene mutation is worse than losing the gene altogether. Thus, a single gene mutation may be very important to the rare individual with the mutation, but not reflective of the general syndrome. 22q13 deletion syndrome is a chromosomal deletion syndrome.
Even small terminal deletions cause a major loss of genes
What most people do not understand about chromosome 22 is that the 22q13 area is rich in genes near the terminal end. That is, deleting a small part of the end removes a lot of important genes. Here is a chart based on the most complete published study to date (Sarasua et al., 2014) and the most complete listing of genes available.
(Right click on the graph and open to a new window to see it full size.)
The graph has two lines drawn across 22q13. The scale on the bottom is distance from the end of the chromosome. Zero is the terminal end of the chromosome. The numbers 1 through 12 are 1 to 12 megabases (M base) from the terminal end. The line in blue, shows how many people have a deletion of at least a certain size. For example, about 97% of documented cases of 22q13 deletion syndrome have deletions that are 1 M base in size or larger (red arrow at 1 M base). People with very small deletions are actually uncommon. It is far more common to find people with 1 M base deletions or larger. In green, you can see how many genes are involved with each deletion size. The thick red arrows show that the same 97% of cases are missing a whopping 25% of the known genes in 22q13 part of the chromosome. There are so many genes in the first 1 M base of the chromosome that people with 2, 3 or even 4 M base deletions are really not all that different from each other (horizontal portion of green line between 1 and 4). So, 22q13 deletion syndrome is a syndrome of many genes for nearly everyone.
This chart helps explain why the effects of deletion size have confused people (including scientists) for so long. There are so few cases of small deletions and so many genes, that researchers have never been able to tease out which genes are important (although many unsubstantiated claims have been made). Moreover, larger and larger deletions (2 – 4 M base) seem to have no additional effect. Although confusing in the past, now we know how few genes reside between 1 and 4 M bases from the terminus of the chromosome. It makes sense given the shape of the green line.
You might ask, what kind of genes are in the “gene rich” 1 M base part of the chromosome? Are they important to the hallmark trait of 22q13 deletion syndrome, intellectual disability (cognitive dysfunction)? The answer is a resounding, yes! There are 31 genes in the first 1 M base and 10 of these are related to brain function. Thus, 97% of 22q13 deletion syndrome patients are missing 10 or more “brain genes”.
The 22q13 region has at least 19 different genes that affect the brain and 10 reside in the terminal 1 M base region. These genes sculpt the developing brain, protect it from damage, regulate excitability (e.g., avoid seizures), maintain healthy tissue and regulate cell death. In my next blog I will discuss one brain gene that is lost in 100% of all terminal deletions. It is a very special gene. This gene is found only in advanced primate species (e.g., humans, chimpanzees). Moreover, it has a unique, specialized role in the human brain. This gene is as special as the human brain itself. When you think about what makes a human special, you think about intellectual ability, sophisticated social interactions, symbols, language and future planning. The expression of this gene evolved in concert with our uniquely human qualities. You cannot find a more special brain gene than that! Stay tuned.