Looking for opportunities

David 11 March 2017 small
Six years to learn walking, 9 years before eating by mouth. This picture seems so ordinary, but his parents see more than meets the eye.
Originally posted 10 March 2017
Updated 16 January 2022
Available in Portuguese  https://pmsbrasil.org.br/procurando-oportunidades/

Success is very much about seizing opportunities. With all of David’s early issues caused by his Phelan-McDermid syndrome (PMS), we could not address everything at once. That said, we always looked for opportunities. For example, when he started climbing in the refrigerator we encouraged him to climb (under watchful eyes). See the picture here: Gene deletion versus mutation.

Like raising a child with a serious genetic disorder, science is about hard work and seizing opportunities. The discovery of penicillin is a classic example.  Alexander Fleming made his discovery in a moldy petri dish. The open dish left sitting in the sink was contaminated by a mold that killed bacteria in the dish. The mold in the dish was accidental, but Fleming’s observation was not. He was a scientist looking for ways to kill bacteria. A few years after the initial discovery, penicillin saved its first life: a child. We need to keep our eyes open for opportunities and we need to make the most of these opportunities. So how can we do that with PMS?

In March of 2017 a group of parents took on a challenge. I asked them to identify other children with PMS who were most like their own child. The goal was to find ways to “cluster” the characteristics of children with PMS, as described in my blog: Splitting, Lumping and Clustering. It was a lot of fun and, just as I suspected, there are groups of kids that are very similar to each other. The exercise on Facebook was an example of crowdsourcing. There are people who are experts at crowdsourcing studies. I would recommend someone expand this exercise into a real study. There is a lot to learn. Parents have insights into their children that medical researchers cannot. Categorizing how groups of children are alike and different could accelerate research, should someone want to take the opportunity

This blog is about untapped opportunities to look at categories of PMS (also called 22q13 deletion syndrome). There are special cases we should not overlook.

Matched deletions

I hear people say that no two deletions are exactly alike. That is not true. There are special cases where the deletions are exactly the same: 1) twins (yes, there are twins in our community), 2) unbalanced translocations (my son’s deletion and my niece’s deletion are exactly the same, as are several other children and adults in our extended family), and 3) germline deletions. I do not know any PMS family with multiple children from germline deletions, but I suspect they exist. In addition to exact matches, there are deletions in regions of the chromosome that have few genes, or few genes that affect the central nervous system. In these cases, nearby deletions may be equivalent in terms of genetic loss (see Understanding Deletion Size).

I have heard some physicians and scientists say “no two deletions are alike” even though they should know better. We need to exploit these cases to find out what matched deletions have in common and how they differ from each other. Those observations will hint at which aspects are purely due to the genes deleted and which are due to more complex interactions between genes and the environment. We need a more nuanced understanding of PMS.

Interstitial math

Most known cases of PMS are associated with terminal deletions of chromosome 22. “Interstitial deletions” (I call PMS Type 2) are far less common. What if we take each person with an interstitial deletion and compare them directly with those who have terminal deletions that start at the same spot on the chromosome? In such comparisons, both people would be missing the same interstitial genes, but not the remainder of the genes. What can we learn? It is a kind of A minus B experiment. It might or might not be very informative, but we won’t know until we take the opportunity. The data are already available in the PMS DataHub.

Pure SHANK3 deletions

If one copy of the SHANK3 gene is missing altogether and no other genes are affected, that specific case can examine the impact of loosing just the SHANK3 gene. But this specific circumstance (a pure SHANK3 deletion) is very rare and not systematically studied. I feel someone should take the opportunity to study these cases systematically. So far, there are studies of larger deletions with attempts to compare different deletion sizes. That is a helpful approach, but not quite the same. There are also scientists who argue strongly that pathogenic SHANK3 variants (sometimes called SHANK3 “mutations”) act simply by reducing the amount of SHANK3 protein. The theory predicts that pathogenic SHANK3 variants are the same as losing one copy of the SHANK3 gene, and nothing else. But the theory has not held up to scientific testing.

Various studies show that pathogenic variants of SHANK3 likely disrupt special “isoforms” of SHANK3 during fetal development, or may disrupt the normal operation of SHANK3 protein in the adult. The difference between having insufficient SHANK3 protein and having an errant (interfering) version of the SHANK3 protein, is important. Oversimplifying the effects of pathogenic variants may lead us down the wrong path when seeking ways to treat people with PMS.

There are opportunities to study the difference between deletions and variants. I describe this in my blog Gene deletion versus mutation. We need a study that specifically compares these two groups: people with SHANK3 mutations and people with complete (or nearly complete) SHANK3 deletions that are specific  enough to leave other, nearby genes, alone.  Once again, we parents seed these opportunities with family data in the PMS DataHub.

Where next?

I believe parents can be major contributors just by our ability to see similarities and differences in our children. The scientists and clinicians studying our children have all kinds of ideas, but frankly they can use a little guidance. I am not a fan of drug studies that mix kids with different pathogenic variants and different deletion sizes without first making the comparisons I have listed. There are more opportunities. We need to encourage greater discussion on the potential role of each important gene of PMS (see Which PMS Genes are Most Important).

Not every parent is interested in the detailed science. But, I encourage parents who take an interest to learn about the genes I discuss in my blogs. I also encourage scientists to think more critically about PMS. It is not a disorder of just one gene, and even in the cases of pathogenic variants of SHANK3, PMS may be a far more nuanced disorder than one of haploinsufficiency. We should always be looking for opportunities to address central questions, and we should always be cautious about our assumptions.


Some previous blogs

Splitting, Lumping and Clustering
Defining Phelan McDermid syndrome
Why don’t we have better drugs for 22q13 deletion syndrome?
What do parents want to know?
Is 22q13 deletion syndrome a mitochondrial disorder?
Educating children with 22q13 deletion syndrome
How to fix SHANK3
Have you ever met a child like mine?
How do I know which genes are missing?

Mouse models
How can the same deletion have such different consequences?
22q13 and the hope of precision medicine
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
22q13 deletion syndrome – an introduction


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