Originally posted 20 May 2015
Updated 3 April 2021
Available in Portuguese http://pmsbrasil.org.br/sindrome-da-delecao-22q13-uma-introducao/
Definition of 22q13 deletion syndrome
22q13 deletion syndrome has been defined different ways. Here is one that was on Wikipedia for a long while:
“…a genetic disorder caused by deletions or rearrangements on the q terminal end (long arm) of chromosome 22.”
In some research reports the role of one gene (out of 108 genes that may be deleted), SHANK3, is emphasized.
22q13 deletion syndrome is often called Phelan-McDermid syndrome (PMS) or Phelan-McDermid deletion syndrome (PMDS). 22q13 deletion syndrome was first observed as a terminal deletion of chromosome 22 (Nesslinger et al., 1994). Other major deletions in that region are still considered 22q13 deletion syndrome by some, but not by others (for example, see this letter to the editor). The term PMS was introduced by The Phelan-McDermid Syndrome Foundation, which adopted that name for the Foundation. An attempt to build a scientific consensus on the definition of PMS in 2012 ended in disarray. I am told that new discussions have been underway since early 2020. As of 2021 there has been no announcement from the Foundation.
Different scientists and clinicians often use the term PMS differently. Some use PMS to describe any intellectual disability or autism caused by deletion or mutation of SHANK3, excluding cases of interstitial deletion or pathogenic variants of other genes. For example, “…deletions and mutations that lead to a loss of a functional copy of SHANK3 cause Phelan-McDermid syndrome” (Betancur and Buxbaum, 2013). This follows the “SHANK3 hypothesis of PMS”, which is widely cited, but as yet, unproven. Other experts in the field define PMS as deletion or mutation of any gene(s) in the 22q13 region, as long as the individual presents with manifestations typical of 22q13 deletion syndrome: “Almost all of these deletions include the gene SHANK3…” (Original text of Phelan and McDermid, 2012, strangely, it was changed by the editor more than a year after publication). When this blog was originally written (May of 2015), the Foundation web site (http://22q13.org) avoided a detailed operational definition. Rather, it described “typical causes” that focused on SHANK3, somewhat echoing the SHANK3 hypothesis of PMS. This blog space discusses the roles of SHANK3 and the other 107 genes that are involved in deletions that lead to 22q13 deletion syndrome. It goes into great detail and discusses the science behind each relevant gene. Along the way it teaches three things related to science: 1) the science behind our understanding, 2) how science works and 3) the human component of scientists doing science.
Science, medicine and PMS
My son, David has a 22q13 deletion, but he also has an overdose (trisomy) of chromosome 19. Is that PMS? Who knows? Most people say “yes,” but it is hard to diagnose without a consensus definition. This brings into focus the role of clinical geneticists. They operate under certain principles and rules, although somewhat different rule sets prevail in different settings (e.g., U.S. versus European). Recently, I was asked by a mother to make sense of a genetic report from a prestigious university-affiliated hospital. The report had errors owing to the confusion between what constitutes PMS and the phenotype characteristics of 22q13 deletion syndrome. Because of those errors, the recommendations were flawed. Another parent showed me their child’s genetic report with a conclusion that seemed absurd. It centered around the problem of guessing whether or not a radically different version (“variant”) of a gene interfered with the gene’s normal function.
In fact, much of medical genetics is guesswork. One goal of my blog is to inform parents, scientists and clinicians. I separate facts from conjecture. I introduce concepts from the latest scientific studies and how they may apply to PMS. The scientist’s perspective is often very different from the clinician’s, especially when it comes to genetics. Of course, the parent’s perspective is different from the others. Parents mostly interact with clinicians. This blog is an opportunity for parents to incorporate science into understanding their child’s disorder. Very few geneticists ever see even a single case of PMS. Faced with a potential case of PMS, a geneticist may read one or two sources and then render his/her professional decision. Unbeknownst to the geneticist, the sources may not be ideal selections for the case in front of them. This blog will supply a more complete view of PMS to help guide their research and their decision making. Scientists who study PMS see the disorder from either a technical perspective, or as a clinical practitioner. Living the life of a PMS parent paints a different picture. It is a case study (my child) in unfathomable depth and under infinite magnification. Scientists need to hear from parents. Rarely does that occur in the vernacular of science. Scientists have much to learn from parents who speak their language fluently.
This blog space
As with the definition of PMS, much of science can be messy. Most discussions of science oversimplify the realities. This blog is dedicated to those parents, clinicians and researchers who try to make sense of genetic defects that can arise from the q13 region of chromosome 22, whatever you call it. It is aimed at parents who live with it and deal with it every day. It is for anyone who wants to understand more. All sources of information are biased and perhaps my bias suits you, or at minimum, is informative.
There are only about 2 to 3 thousand identified cases of 22q13 deletion syndrome world-wide. That leaves little opportunity to find a parent who has raised a child and is also a scientific expert in the field. There are a few. As one of the few, I felt obligated to start a blog. So, that is what I have done. You can click on Who is arm22q13 to learn a little more about me or explore my social media profiles listed below. Please read this disclaimer and keep it in mind as you read my blog posts. When I write my blog, I am not a representative of any organization. I represent only myself.
This blog will be full of statements: scientific, personal, experiential, opinionated, political and maybe even hostile. All of the statements are mine, alone (except when explicitly indicated otherwise). None of these statements are to be taken as a reflection of my employer or any other organization. I make no pretense of representing any organization or employer. Any errors, misstatements, wrong facts, wrong attributions or other misdeeds are my sole responsibility. One of my past employers is an agency of a government. I do not represent or speak for the agency or the government either on or off the record. This blog is a personal undertaking for the benefit of my fellow parents who must deal with the often painful reality of raising a child with 22q13 deletion syndrome. They deserve all the help and love we can offer.
7 thoughts on “22q13 deletion syndrome – an introduction”
Hi, thanks for sharing my son is Jared 22q13.3 diagnosis at age 3 in 2004 only 150 children had be identified. I am out of the lope in new advance but would love to know more of what changes to help shape are kids future! Thanks for your blog
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I hope you find some of what you are looking for reading this blog. We all wonder about our children’s futures. I think you will get some hints when you read some of my future posts. I have not thought about writing an article on adults with 22q13 ds, but that might be a good idea. Thanks for your input!
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Just recently found out my son is diagnosed with PMS, and he is 45 years old, a faternal twin who was 3 lbs. and had developmental delays from beginning, but at that time told “sign of premie”. He strugggles alot with developing friendships and expressing himself well.
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We did not find out until David was 15, so I appreciate the experience. There are a some good Facebook groups for PMS parents, including an adult one.
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Descobrimos que nossa filha Caroline tem a síndrome de Phellan Mc- Dermid quando ela tinha 8 anos, até hoje são muitas dúvidas e muita dificuldade em acertar medicamentos para crises convulsivas severas.
David has mild seizures that are well controlled with medicine. I know some children with PMS who have seizures that cannot be controlled well with medicines. It is a very difficult circumstance.
Thanks Andy. Matthew is so similar to David in what you describe about walking and balance. Plus many head injuries as a child. Broken nose several times. Thankfully his joyful spirit endures.