Can 22q13 deletion syndrome cause ulcerative colitis?

ItalianoAndrew holding David cropped

David at age 6 months with with oxygen and feeding tubes

Originally posted 30 May 2015
Updated 24 September 2022

From a parent’s perspective, one the the most challenging and painful experiences is watching your child suffer. Sometimes, we don’t even know how much distress our child is enduring until after the fact. Once, when David was quite young, I heard something funny going on in his crib (pictured above). When I looked closely, he was swallowing over and over, gasping for breath in between each swallow. I realized his nasogastric feeding tube had slipped partway out and he was doing his best not to choke on the food being pumped into his throat. Years later, I remember removing David’s shoe after school and discovering that his sock has slipped off his foot. The sock was scrunching his toes in the shoe. His toes were very red and swollen. Every step that day at school must have been painful.

Raising a nonverbal child with multiple problems can be heartbreaking. How often do our children suffer from painful medical conditions? How much does undetected pain cause sleep disturbances? How much poor behavior or failure to learn stem from painful medical conditions? We don’t know, and that keeps me up at night when David does not.

If a child with 22q13 deletion syndrome (Phelan-McDermid syndrome, PMS) has a deletion size of 1 Mb or larger (about 90% of patients), he or she is missing at least 30 genes (Sarasua et al., 2014). That is a lot of genes, considering that damage to only one or two genes can sometimes have devastating consequences. Some of these genes are strong candidates for causing serious problems (see Which PMS genes are most important?). Other genes, like IL17REL, may contribute to the disorder in uncomfortable ways. PMS children undoubtedly have things going wrong inside their bodies.

IL17REL and ulcerative colitis

Around 2005, scientists started using relatively new genetic tools to dig into the connection between genes and disease. PMS was discovered using earlier tools that looked at broken chromosomes (Phelan et al., 2001).  Newer tools allow researchers to look at single genes or small regions of the chromosome. IL17REL sits about 1 Mb from the end of chromosome 22. It can confer risk for ulcerative colitis (Franke et al., 2010; Sasaki et al., 2016), a form of inflammatory bowel disease closely related to Crohn’s disease. Ulcerative colitis is an autoimmune disease, meaning that the body’s own defenses are somehow attacking or otherwise injuring the body itself. From everything I read, ulcerative colitis is the kind of disease that causes a lot of discomfort: chronic, invisible pain. My son, David, is nonverbal. When he is behaving badly it is often associated with something wrong in his world. Chronic discomfort and lack of communications can add up to sleepless nights and poor behavior.

Very little is known about how IL17REL contributes to ulcerative colitis. The cases described in the two papers were gene variants, not gene deletions. Variants can sometimes be worse than deletions (see Gene deletion versus mutation (variant): sometimes missing a gene is better). The variant may interfere with normal protein function, which is not quite the same as loosing a copy of the gene.

We know the IL1REL protein probably activates IL-17RE receptors along with the better-studied cytokine IL-17C. IL-17C is associated with psoriasis, another autoimmune disease (Martin et al., 2013). In healthy animals, IL-17RE receptors operate in the colon to defend the body from bacterial infections. In rats, losing IL-17RE receptors lowered the rat’s natural defenses and lead to infections and death (Song et al., 2011). One might guess that losing IL17REL, as with PMS, could reduce the body’s ability to fight GI infections. Thus, problems with the IL17REL gene could lead to ulcerative colitis (overactive) or more frequent GI infections (under active). Either way, problems with this gene could lead to great discomfort.

Other missing genes may make things worse

People with PMS who are missing IL17REL are also missing other genes. MAPK11 and MAPK12 are examples. These two genes are associated with cytokines and, to some degree, ulcerative colitis (see review by Feng and Li, 2011). There is very little research on how missing multiple genes impacts a disorder like PMS. Does the loss of other genes exacerbate the loss of IL17REL? We don’t know.

A question of ethics?

So far as I can tell, there is no targeted research on IL17REL, MAPK11 or MAPK12 in children with PMS. Should the potential for chronic, invisible pain be of interest to families? It is certainly a topic interesting to me. Does missing all three genes contribute to recurring symptoms in our children? I would like to know. Perhaps the bigger question is, how many other genes (or groups of genes) could be causing chronic, painful conditions? From a purely humanitarian point of view, a serious discussion about genes that may cause chronic pain is long overdue. Maybe we need a search for “potentially painful genes” of PMS. David cannot tell me what hurts when he does not feel well. Our children count on us to know when something is hurting, and at least try to fix it.


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