Is “PMS-SHANK3 unrelated” truly unrelated to SHANK3? Maybe not.

David relaxing in the car during a drive through the countryside

Originally posted 10 April 2024

In 2022 a group of scientists associated with the Phelan McDermid Syndrome Foundation (PMSF) published a consensus paper that addressed a controversy around what constitutes Phelan McDermid syndrome (PMS). It was an important step toward defining the disorder, providing guidance to geneticists, and working towards an ICD code for diagnosis and medical reimbursement. Although the consensus opinion was not universal, the clarification was welcome. These experts split PMS into two mutually exclusive classes: “PMS-SHANK3 related” and “PMS-SHANK3 unrelated”. It is a simple, clear dichotomy. But genetics are rarely simple, as we shall see.

The thinking at the time was from the perspective of genetic testing. If the test result includes an abnormality of the SHANK3 “coding region”, then it gets the designation PMS-SHANK3 related. All other test results would be PMS-SHANK3 unrelated.

The people who hammered out this definition (distinction) are all experts. They were fully aware of all the possible ways genes can contribute to a disorder. There are dissenters, also experts, who feel that if SHANK3 is not involved, then the name PMS should not be applied. The consensus paper explains that people with interstitial deletions (PMS-SHANK3 unrelated) do not appear to have a syndrome different from PMS. There is also no transition from PMS to some other syndrome as deletion sizes get larger, whether or not SHANK3 is involved. There is no clear evidence that PMS-SHANK3 unrelated is some other type of disorder. The key concern for dissenters is that genes other than SHANK3 do not contribute to the disorder in the same way that SHANK3 causes PMS.

However, what if we can show that other genes on chromosome 22 contribute to PMS through their impact on SHANK3, or their impact on the molecules that interact with SHANK3? If the genes of 22q13.3 (the site of interstitial deletions) have such direct impact on SHANK3, then perhaps the term “PMS-SHANK3 unrelated” is misleading. If the biology of PMS-SHANK3 unrelated is highly related to SHANK3, then a distinction may not be warranted. The latest evidence suggests there are at least six genes that impact SHANK3 (and partner molecules), and these genes contribute to PMS when deleted. I would call these genes SHANK3 related.

The six genes and the details of how they interact with SHANK3 are discussed in a recent paper. The paper is open source (anyone can read it), but very technical. Full disclosure: I helped write the paper, so this blog post is undeniably biased. People who have read my previous blog posts should know that I have long been a proponent of looking closely at the many genes of PMS. The paper is a review of work done by scientists primarily between 2017 and 2024. Science is a continuous process and during this period enough information came to light to explain the tight relationships between six genes (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, TCF20) and SHANK3. The first two genes are physically close to SHANK3 on chromosome 22, and thus are deleted in most deletions that include SHANK3. The remaining four genes are fairly evenly spaced across the last 4 Mb (megabases) of the PMS region of chromosome 22.

I have written blog posts about all of these genes at one time or another. I identified PLXNB2 and PHF21B in Why PMS is worse for people with larger deletions, and PMS Gene PHF21B is critical for normal brain development. I wrote about TCF20, a gene that has long been associated with intellectual disability (TCF20 may explain why some big deletions are worse than others). I have flagged the potential importance of BRD1 in several blogs (e.g., Regression and psychiatric dysfunction in PMS). CELSR1 was highlighted in CELSR1: Do some people with PMS have more fragile brains? SULT4A1 has also been on the radar for some time: New science: SULT4A1, oxidative stress and mitochondria disorder. My message has always been that genes important to PMS will emerge once there was sufficient evidence to critically explain why larger deletions have greater impact. SHANK3 has always been the most important gene and it has been the most intensely studied, but from the beginning of PMS research, it was never the only important gene. By “important” I mean important to families.

All seven genes (including SHANK3) impact brain development and all are involved with the process of inflammation. In this case inflammation includes “cellular stress”, “mitochondrial function”, and “recovery from injury”. These are all related processes, and all known to exacerbate PMS. So, impact on early development and response to stress and injury are features common to all of the genes.

Three of the genes (BRD1, PHF21B and TCF20) regulate what other genes do in the brain. For example, all three regulate the activity at synapses, the part of neurons that SHANK3 regulates. In addition, two more genes (PLXNB2 and SULT4A1) are directly involved in synaptic function. In fact, SULT4A1 not only regulates the same glutamate receptor as SHANK3, but it also regulates breakdown of SHANK3 at the synapse.

At this point it should be clear why PMS-SHANK3 unrelated may not really be unrelated to SHANK3. The six genes listed above join SHANK3 in shaping the development of the brain, the response of the brain to insults, and the operation of the synapses – the most important role of SHANK3 in the brain. It should also be clear why people with interstitial deletions typically have symptoms consistent with other cases of PMS. Likewise, it should also be clear why people with larger and larger deletions tend to have more severe PMS (see: Why PMS is worse for people with larger deletions).

The very close association between SHANK3 and at least six other PMS genes has a number of ramifications. First, while the distinction between SHANK3-related and -unrelated is sensible from the point of view of genetic testing, it may not be a good way to think about PMS as a disorder. Second, treatments that target SHANK3 will likely miss other relevant genes that tightly influence SHANK3, and thus may not produce very satisfying results in patients with chromosomal deletions. One way to think of the problem is that SHANK3 treatment in people with deletions essentially expands the number of PMS patients with interstitial deletions. It may be difficult to distinguish between a treatment that is not effective for SHANK3, and a treatment that is not effective because of other genes. Finally, when we are searching for an effective treatment for SHANK3 haploinsufficiency, maybe we should also look at treatments for one or more of the other genes. We may be missing out on developing additional valuable treatments.

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