When I get on Facebook I look for pictures of our 22q13 deletion syndrome kids. Every time I see one I give it a “thumbs up”. It warms my heart to see other parents share their pride in their children, even if our children are peculiar in some way. Our snapshot may capture a funny posture or gait. David is almost always looking away from the camera. Some 22q13 kids are captured chewing on “non food items”. We post photos to show our pride in accomplishments that would have been easy for most other kids. Our children are usually not very photogenic, except to families and, of course, other parents of kids with 22q13 deletion syndrome.
There are some pictures that we don’t put on Facebook in deference to families that could not appreciate them. There are pictures of feces on the sofa, self-inflicted injuries, frightening hospital scenes, and even pictures after an early death. The reality of 22q13 deletion syndrome is often not pretty. However, our goal is not to provoke a reaction. We simply want to share joy or commiserate with our community, like all parents.
David, like the overwhelming majority of children with 22q13 deletion syndrome, has many things wrong. He is missing more than one or two genes and the impact is pretty obvious. Ninety-seven percent of children with terminal deletions are missing from about 30 to 200 genes (see Understanding deletion size). Science can help us find ways to help our children. The first step is to find out which gene causes which problem. Fortunately for our children, science has a bunch of relatively new tools to help create this “genotype-phenotype map“.
This is a list of genes organized by deletion size. The deletion size on the left corresponds to the list of missing genes of the same color on the right. A 1 Mb deletion will delete all genes in dark brown, starting from RABL2B and ending with ALG12 (33 genes). The next group (reddish brown) are missing if your child has terminal deletions of 5 Mb or more (16 more genes, giving a total of 49 genes). That covers about half of all common terminal deletions. Terminal deletions have been observed for sizes up to about 9 or 10 Mb. The genes above that are usually missing only with certain interstitial deletions.
Ok, so now we have our list. The crucial question is, which genes do what? In the past few years scientists have built some rather clever and remarkable tools for figuring this out. Here are some tools and some examples of how they can be used.
Comparing 22q13 genes with known genetic syndromes
Online Mendelian Inheritance in Man (OMIM) is a database of genes and the problems associated with them. By choosing a trait like poor body temperature control (poor thermoregulation) or low muscle tone (hypotonia), you can find out what genetic disorders have that feature. From that information, you can identify which genes are involved. Sound complicated? Not at all. If you go to the Human Phenotype Ontology web site and type in “abnormal muscle tone” it does the entire cross-reference in a few seconds. Click the tab for “genes” and you get a list. I did just that. I found which genes match the list of 22q13 genes and highlighted them here.
What is interesting about this list is that only two genes are directly involved with the synapses of the brain (SHANK3 and MAPK8IP2). Other genes linked to hypotonia have other important functions. One gene is important for the synthesis of neurotransmitters (SULT4A1). Some genes affect white matter and peripheral nerves (ARSA and SBF1). Another gene affects the muscles directly (CHKB). Some genes affect many organs (ALG12 and NAGA). As I see it, each gene is an opportunity to find a treatment for our children. If one gene is complicated and hard to study, there are other genes that might lead more quickly to important benefits, like new treatments.
Comparing 22q13 genes with genes that work specifically in the brain
If we are interested in behavioral problems and intellectual disability we can benefit from a recent scientific study that has created a list of genes that are specialized for the brain (Pandey et al., 2014). Using a “gene expression atlas,” these researchers identified genes that are either used (expressed) at a very high level in the brain, or used much more in the brain than anywhere else. The logic is simple, if the brain treats these genes as important, then they must be important.
Only 4 genes show up. These are obviously 4 genes that deserve careful research to help people with 22q13 deletion syndrome. Two of these genes, MAPK8IP2 and SULT4A1 also appeared in the hypotonia gene search.
Comparing 22q13 genes with genes that evolved for a specific purpose
One of the most interesting new methods for understanding the role of genes comes from the study of how humans evolved. I have already written about the value of this approach (see Is 22q13 deletion syndrome a ciliopathy ?). There is an interesting website that automates the process of studying evolution. This approach, called “forward genomics” is more difficult to use than the previous two examples, but this method may solve some important problems. I am very interested why David gets too hot in the sun and too cold after a bath. That is, why does he have problems regulating his body temperature. By studying the scientific literature on which animals are good at body temperature regulation and which animals are not, this web site will tell me which genes are involved. My job is to read textbooks and papers to find out how well each of 27 species of animals regulate their temperature. Once I do that, I can ask the website to scan the genomes of these species and identify which genes are associated with the emergence (or loss) of the ability to regulate body temperature. It is a fascinating approach and I am very eager to learn the results. The results may open the door to lowering the risk of febrile seizures.
There are other methods for finding genes that affect our children in specific ways. For example, gastroesophageal reflux was such a serious problem for David that he required major abdominal surgery (Nissen fundoplication). A comparison of reflux with known genetic conditions (similar to the hypotonia example) provided no new information about 22q13 deletion syndrome genes. However, the search did produce a list of 48 reflux genes. How can we use the reflux gene list to learn more about 22q13 genes? First, there is an analysis method called “guilt-by-association“. This analysis will indicate which 22q13 deletion syndrome genes naturally operate in concert with the reflux genes. A even more complex analysis tool for protein-protein interaction can identify which 22q13 genes have chemical interactions with reflux genes. I expect one or more 22q13 deletion syndrome genes will be associated with reflux after these analyses.
Tremendous progress has been made in the understanding of how genes contribute to disorders. The best way science can help our children is by identifying the many different genes that cause the many different problems. That is Step One and modern methods make that step much easier and more informative that the old methods of the past. Step Two is to find treatments. Many of these genes have been studied in great detail. Some have related treatments either already in use or suggested by researchers. As a parent, I want to see new treatments found for David. As a researcher, I don’t understand why we are not taking these potentially fast tracks to treatment.
22q13 Deletion Syndrome: hypotonia
Understanding gene size
Gene deletions versus mutations: sometimes missing a gene is better.
Is 22q13 deletion syndrome a ciliopathy?
Understanding translocations in 22q13 deletion syndrome: genetics and evolution
Understanding deletion size
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction