Jannine Cody, the parent/scientist who studies 18q deletions, says that since every deletion is different, every child with a deletion is different. At the PMS family conferences we met other children with 22q13 deletion syndrome who, at the time, had striking similarities with David. These children had chromosome 22 deletions of various sizes, and similar children did not always seem to have the same size deletions. We know now that genes are not distributed equally along 22q13, so children with small deletions can be quite different from each other, and children with large deletions can be quite similar (see Understanding deletion size). We also know there are good scientific reasons to expect differences (see How can the same deletion have such different consequences?). Some things are pretty obvious after a while. The kids who could not walk or talk generally had larger deletions. Those with larger deletions also had many more medical problems. Obviously, more genes lost means more problems. Regular readers of this blog have seen evidence of why it is very important to know which genes are missing (see How do I know which genes are missing?).
Some people feel that research on 22q13 genes should be done one gene at a time, starting with SHANK3. I am not a big proponent of this approach, since it ignores a lot of research already done on ARSA, MAPK8IP2, CHKB, CPT1B, PANX2, ALG12, BRD1, SULT4A1 and other genes known to cause disorders in humans, mice or both. The one gene-at-a-time approach also slows research by making one gene sound much more important than others. It seems to me if we spend 5 to 10 years on each gene, we are doomed to spending 500 to 1,000 years. If that sounds pretty absurd, well, it is. Maybe it will only take 200 years to do it this way. That still seems too long to me. That is why I recommend the scientific program be managed by someone with a deep understanding of science leadership (see 22q13 deletion syndrome and science leadership). The “SHANK3 or bust” research program has succeed in some ways. Recently, after about a dozen mouse models of Shank3, there is a new mouse with the first complete deletion of the gene. All the other mice were various examples of gene mutation. As we know, the effects of mutation (or removing part of the gene) can be very different from deletion (see Gene deletion versus mutation: sometimes missing a gene is better). This is critically important! The main reason for supporting Shank3 mouse research is the argument that most (not all) patients are missing the SHANK3 gene entirely. Thus, it is SHANK3 deletions that make the research important to our families. (Note that mouse Shank3 mutation research has a very separate goal: understanding how mutations might contribute to general forms of autism.)
So, we now have a real Shank3 deletion mouse and everyone is very excited about it (Mouse Model of Autism Offers Insights to Human Patients, Potential Drug Targets). Of course, be skeptical of what the university PR team says (see Mouse models). Let’s take a look at this first-ever complete Shank3 knockout mouse. First off, the major finding is that this mouse is different from the many mutation mouse models. No one should be surprised. What is surprising is that you have to completely wipe out 100% of Shank3 to see a measurable difference between these mice and normal mice. Even more shocking is that these mice are walking around, playing with other mice, eating, talking mice talk (ultrasonic sounds) with no shank3 whatsoever in their bodies! The mice missing 100% of Shank3 are different from other mice, but mice missing 50% are not different in any measurable way. Note that humans with 22q13 deletion syndrome are missing only one of the two genes and best evidence is that they have lost only about 25% of their shank3 protein (See this research paper).
So, is there something wrong with the mouse study? Are mice just way different from humans, or is there another explanation? Maybe it all makes sense. Have you ever met a human missing all of SHANK3 and only SHANK3? The complete knockout Shank3 mouse is best compared with a person like that, someone who is not missing any other genes and has no known mutations. It is not good enough to have someone with a “small deletion”, since there is strong evidence that adjacent genes impact brain function. This mouse models SHANK3 deletion. I have met only one person who seems to fit this description.
Phelan McDermid syndrome is characterized by developmental delays, moderate to severe intellectual disability, little or no expressive language, and infant hypotonia (floppy baby syndrome). Some people argue that the syndrome is also characterized by a high incidence of autism spectrum disorder, although some top scientists disagree. The person I met was probably never a floppy baby, has practically normal speech, and that person has no evidence of autism. Rather, the person I met has some problems with coordination, has a great difficulty learning and is socially a wonderful person to meet and engage with, perhaps to a fault. Tragically, like all of our children, that person will never navigate the world well enough to live an independent life.
In summary, when I read the scientific paper on the complete Shank3 knockout mouse, what struck me was how many tests the complete, 100% knockout mouse passed without demonstrable evidence of a problem. Mice missing one copy are normal in almost every test. Mice missing both copies are not “normal”, but clearly, even these mice are nothing like my son.
How important is SHANK3? It is impossible to make that judgement based on only one clinical case. The person I met has lost all independence for that person’s entire life. That is very important. Moreover, it is tragic. But for 95% of families, 22q13 deletion syndrome comes with the full set of core features of 22q13 deletion syndrome. David cannot tell me when he feels sick, where it hurts, or if he was mistreated in his group home. It took him 6 years to overcome his floppy baby syndrome enough to walk and three more years before he could eat by mouth. His autism-like features interfere with social contact.
As of now, the most parsimonious explanation of what we know is that SHANK3, alone, does not produce the core features of 22q13 deletion syndrome. It is a contributor in most, but not all, cases.
How do I know which genes are missing?
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
Can 22q13 deletion syndrome cause ulcerative colitis?
Can 22q13 deletion syndrome cause cancer?
22q13 deletion syndrome – an introduction