Defining Phelan McDermid syndrome

It is all a matter of how you look at the problem.

Originally posted 4 March 2017
Updated 10 April 2024

It is very hard to talk about and explore, much less cure, a syndrome if you don’t define it first. While 22q13 deletion syndrome seems like it should be straightforward — a deletion of 22q13 — life is rarely that simple. In 2012 I was offered a chance to bring people together to address the question of how to define Phelan McDermid syndrome (PMS). I took the role and opportunity seriously. I decided to make a slide presentation that would set the stage for parents, scientists and clinicians to discuss a definition for the syndrome. As it turned out, the offer was rescinded. Without any modification, I present the final slide from my talk (see figure).  There has been a more recent effort to establish a simple classification (see this blog). However, there remains poor agreement in the field and the catagories, thus far, contribute more to diagnostic criteria than a structure to understand the disorder.

The color coding is important. Things in green are PMS. Things in rust red are not PMS. Dashed lines are just to make it easier to see. The scheme covers nearly every circumstance, including pathology of regulatory sites. The only unaddressed issue is what might be considered phenotypic. It seems to me now that any intellectual disability that is not syndromic in some other way (e.g., metachromatic leukodystrophy caused by the deficiency of arylsulfatase A, OMIM #250100), should be considered the core phenotypic trait of PMS. Regardless, the slide represents the only detailed framework I have ever seen for a definition of PMS.

There is a great interest in SHANK3 and its relationship with 22q13 deletion syndrome. Using the scheme, above, and other information that we know about SHANK3 and 22q13 chromosomal deletions, I recently put together this chart:

In this case, the dashed line indicates that autism spectrum disorder may accompany intellectual disability and still be part of PMS. The chart shows that many SHANK3 mutations are not PMS. They are either nothing (have no phenotype) or some other neuropsychiatric disorder. When 22q13 deletions include SHANK3 (even just a part of SHANK3), they can be PMS. In fact, they are rarely not PMS. Some SHANK3 mutations (pathogenic variants) lead to the phenotypic traits of PMS. Mutations of SHANK3 that confer a different primary phenotype (e.g., schizophrenia or autism spectrum) should not be lumped into the PMS category.

There are other ways to define a disorder, but the worse thing we can do is not define it at all. Developing any classification system is tricky. It is always political. The politics impacts both the science and the families. Even after 12 years, the politics have not been resolved. Perhaps the answer is to have multiple definitions, and identify the definition being used when writing or speaking about the disorder. The definition of this disorder remains in disarray.

arm22q13

Previous blogs

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.
Understanding deletion size
22q13 deletion syndrome – an introduction