22q13 deletion syndrome: the hope of precision medicine

David, the backseat driver
Although non-verbal, David is clearly in charge of this trip.

David does not talk, but he does know how to express himself. In this photograph we are taking a ride to his brother’s apartment.  As soon as I arrived at David’s house, he grabbed my hand and walked me back to the car.  He pulled on the door leading to the back seat.  “Take me for a ride!  The usual place, of course!” He communicates very well considering all his disabilities, but I would love to have a medication to help him talk, or walk better, or toilet easier, or not overheat in the summer.  In fact, what I really want is a custom pill made for David.  Different patients with different size deletions have different needs. Although intellectual disability affects 100% of our kids and ASD affects up to 30%, the reality is that our children can have many different problems.  Except for a few confusing cases, kids with larger deletions have more problems and often more severe problems.

If you read my earlier blog on deletion size (Understanding deletion size), you will know that over 95% of patients with 22q13 deletion syndrome are missing from 10 to over 100 genes.  The genes near the end of the chromosome are the first ones to be deleted by a terminal deletion (the most common type).  These genes are tightly packed together.  In this region, you cannot simply say “a small deletion”.  You must know the exact deletion size to know how many genes are affected.

Precision medicine

According to the National Institutes of Health, “precision medicine” is “… an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person” (from: NIH Precision Medicine Initiative).  The promise of precision medicine has not reached most people because the average patient does not know which genes are most important to his/her health. For patients with 22q13 deletion syndrome, however, the genes that cause the syndrome are obviously the genes of greatest clinical importance.  The primary goal of 22q13 deletion syndrome research should be to maximize the benefit of knowing the exact genes involved on a patient-by-patient basis.  Think: “I want a pill optimized for my child”.   Of course, it is an oversimplification to think about a custom pill, but the NIH definition of precision medicine helps guide us toward more practical thinking.

In my last blog (How do we know which genes are important?) I listed the genes that are likely to contribute to hypotonia.  Categorizing the genes into  clinically meaningful categories provided us with insight into treatment.  Each gene in the list has a known effect on the brain and rest of the body.  Some genes interfere with normal brain function.  Other genes can affect peripheral myelin, a insulator that is needed to transmit information back and forth between the spinal cord and the muscles.  Still other genes can disrupt a muscle’s ability to tolerate sustained work.  Each of these categories provide important information to the physical therapist.  A child with poor sensory feedback from the muscles might be handled differently from a child with poor muscle stamina.  Precision medicine is in its infancy, used mostly in cancer treatment. However, precision medicine for 22q13 deletion syndrome could start today.  Physicians and therapists could readily benefit from a report for each person that brings together an individual’s genetics with the known functions of the missing 22q13 genes.

One might wonder how far this precision medicine idea can be taken.  Well, for next year the White House reports a 215 million dollar initiative for government supported research and promotion of precision medicine (White House Fact Sheet).  Businesses have already invested billions of dollars into electronic health records, the backbone of precision medicine. There is no question that precision medicine will bring major changes to medical practice and patient choices.

Clearing up some misconceptions

It is amusing at times to hear well-meaning parents talk about the barriers to using genetic information to guide treatment. One common misconception is that too little is known about the genes.  Actually, many of the genes have been studied for decades and the research has obvious clinical implications.  For example, at the Society for Neurosciences meeting earlier this month I talked to a young researcher from California who was working on CELSR1 (missing in about 50% of our kids).  He showed that neurons in the hippocampus essential for learning new relationships between events and places (e.g., learning to navigate a new school building or deal with a change in classroom schedule) are disrupted when CELSR1 is deleted.  What he told me next was even bigger news. A researcher in Belgium has been studying mice lacking CELSR1 for years.  It took only one email to that scientist to net a trove of information about CELSR1.  Apparently, CELSR1 is not only important for brain wiring, but also the flow of cerebrospinal fluid (CSF) in the brain. Read that: enlarged ventricles.  A radiologist who evaluates the MRI of a 22q13 deletion syndrome child will someday associate his/her findings with deletion size based on studies like these. After enough MRI reports are collected from enough patients, the association of CELSR1 with ventricle size can be confirmed.  The beauty of precision medicine is that you collect new data for the next generation each time you treat patients in this generation.  Taking your child to the doctor actually helps other patients with 22q13 deletion syndrome. Is that great, or what? For people with 22q13 deletion syndrome, it is knowing the detailed genetic information that will make it work.

Another misconception is that there is no clear relationship between deletion size and the severity of 22q13 deletion syndrome.  Actually, even if there was no clear relationship, it would still be of great value to use our knowledge of which genes are involved in each person.  But, we are sometimes faced with the confusing observation that a few kids with big deletions are more functional than others with smaller deletions.  These apparent exceptions to the rule are examples of how genetics can fool us.  Let’s use two examples to show how important knowing the basics can be.  Reading the scientific literature you can find one or two kids with tiny SHANK3 mutations/microdeletions who are more affected than one or two other kids missing a whole group of genes.  As I discussed in my earlier blog (Sometimes missing a gene is better) a gene mutation is often more damaging than deleting that gene.  Such is the case for specific mutations of SHANK3, ATXN10, CELSR1 and other genes on 22q13.  That is part of the reason I use the term “22q13 deletion syndrome”, which distinguishes deletions from mutations.  The second example is the clumping of important genes on the distal part of the chromosome. Because the genes are not evenly distributed on the chromosome, someone with a 1.5 Mbase deletion and someone with a 2.5 Mbase are actually missing the same genes.  Deletion size is not a measure of gene loss.  It simply provides a map to the list of genes that are deleted.  Comparisons have to be made after making a list of genes.

There are other reasons for a conflict between deletion size and severity of 22q13 deletion syndrome.  One recent study has shown that de novo chromosomal deletions (the most common type) often include mutations and other deletions elsewhere on the chromosome or on other chromosomes.  This more widespread occurrence of genetic errors does not tend to show up in the parents or siblings of a child with a de novo deletion.  That is, a diagnosis is 22q13 deletion syndrome raises the possibility that there are more genetic errors elsewhere in the DNA.  Precision medicine will someday not only include the deletion size, but a list of other genes that show potential issues.  There are other reasons for the unusual cases that I won’t go into, but larger deletions affect more genes and generally cause more problems. Of course, individual differences do matter.  That is why it is called precision medicine.

The future is now

My posting on hypotonia landed me an opportunity to give a guest lecture to a graduate physical therapy class.  The lecture was on the genetics of infant hypotonia.  I ended the lecture with a “hopeful warning” that all of medicine is about to change.  It was a warning, because all clinical practitioners will need to understand the implications of genetics in their practice, and it was hopeful because the lives of patients are about to get better.  It may be a while before we can go to an apothecary for a customized pill, but we can reap benefits today.  Your physicians, nurses and therapists could begin receiving guidance curated from the currently available literature on genes.  Of course, someone has to compile the information.  Perhaps we need to convene a conference that brings together experts on each gene with medical practitioners who would use the information. I have seen a number of conferences for 22q13 deletion syndrome, but none like that.

I should probably get a detailed genetic report for David and combine that with my own readings on his genes so that he can benefit from the promise of precision medicine. I am torn by a moral dilemma. I don’t want to be biased in my pursuit of 22q13 genetics. Whether we like it or not, we are always biased by what our own child needs. Not knowing David’s details is, in a way, liberating. I am hanging out with David as I write this. We are watching the Graceland video with Paul Simon.  If you know the history behind that video, it is a reminder that everyone matters, regardless of their skin color, which is to say, regardless of their genetics.



Previous posts:

How do we know which genes are important
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


6 thoughts on “22q13 deletion syndrome: the hope of precision medicine

  1. Andy,

    Wow! It is exciting to learn about the idea of precision medicine and the implications for the future of our 22q13 deletion children (and if not in time for our children, for the next generation). I very much appreciate the scientist in you who pauses to get a detailed genetics report on David so that you don’t bias your research into understanding 22q13 deletion syndrome. However, each of our children’s genetics, while different, likely contain a lot of overlap as well, as you have noted throughout your various posts. Therefore, I say go for it with David’s report. Even if the results bias you toward particular genes,etc., I suspect that bias will also be in the favor of my son, Dane, and many other children. Dane is nonverbal, extremely limited in his ambulation, in diapers, has seizures, loves music, can give you a look that communicates a wish (or annoyance), and so on. Sound familiar?


    Liked by 1 person

  2. What would the method of action be, for a customized pill? Would it repair the deletion or mutation? Would it modulate the functioning of the affected cells or higher level biological processes?

    Liked by 1 person

    • That would be determined on a gene-by-gene basis. One existing medication has been suggested for MAPK8IP2. Some genes, like BRD1 might require a small molecule that interacts with methylation sites on DNA. An actin-targeted drug has been suggested for SHANK3. There may already be a drug to help with certain mitochondrial insufficiencies. Some genes are going to be tough nuts to crack. Some treatments might have to be done in the womb, because the related genes affect early development. I don’t think anyone would want to do gene editing in humans yet, but a viral transfection of a missing gene might be on the horizon.


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