Why PMS is worse for people with larger deletions

David is uses an adaptive switch to compensate for his poor coordination

Originally posted 27 December 2022

It is colder during wintertime

No one in the continental US would say that the autumn is colder than the winter. There are some days during the autumn that are colder than some days during the winter. But, winter is colder than autumn. Phelan-McDermid syndrome (PMS) is much the same. After many years of study, the scientific consensus is clear. Larger deletions come with greater loss of function, even though there are some cases of small deletions having greater impact than some cases of larger ones. The problems with larger deletions come in many forms. In the most recent study, people with very small deletions or only SHANK3 variants had “fewer delayed developmental milestones and higher cognitive ability”. People with larger deletions were “more likely to have a variety of medical features, including renal abnormalities, spine abnormalities, and ataxic gait” [1]. These same larger deletions greatly disrupt the genetics and profile of immune cells in the blood [2]. The whole genetic profile and metabolism of people with deletions greater than 1 Mb is off kilter: “DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two … distinct clinical subtypes of Phelan-McDermid syndrome” [3]. These new studies have only served to validate what was originally shown nearly 10 years ago [4].

What do scientist look for?

While scientists affiliated with the Phelan-McDermid syndrome community have focused largely on the SHANK3 gene, many scientists outside this community have been quietly advancing our understanding of other critical genes of PMS. I have written blogs on some of these important genes, including CELSR1, SULT4A1, TCF20, PHF21B, and others. When it comes to the core symptoms of PMS, which are all associated with brain dysfunction, three aspects of a gene are important to understand. First, what problems are caused by losing the gene in humans and model animals? Second, what biological impact does losing a gene have during early (pre-natal) development? Third, what role does the gene play in the adult human/animal?


When the same gene can impact a person in multiple ways, that is called pleiotropy. For example, losing SHANK3 can cause multiple problems, including low muscle tone, slower or less reaction to pain, GI disturbances, psychiatric illness, and regression. SHANK3 is said to be a pleiotropic gene. Multiple problems can arise from a single gene that gets used at different times in different places. When we think about different times we usually think about how a gene is used during prenatal development, a process that occurs only once in life, and how the gene gets used after birth. Prenatal development lays down the architecture of the brain. In humans, development of the brain continues into the 20s, but the most rapid changes occur before birth. Rapid, but slower changes continue during the first 3 years of life. Things like movement and language rapidly develop in the first few years. But, these changes depend upon the framework laid down in the uterus.

SHANK3 is active during prenatal development. It is involved with axon guidance, the process that neurons use to find each other during development [5] and other processes in early development [6-10]. These processes are distinct from how SHANK3 contributes to synaptic function in the adult brain.

What has come to light in the past few years is the pleiotropy of other PMS genes that contribute both during brain development and in the adult brain.


One gene that is getting a lot of research attention is PLXNB2. From 2007 through 2014 a series of papers describe how Plexin-B2, the protein produced by the Plxnb2 gene as studied in mice, is critical for normal brain development [11-13].  In 2017 it was shown that the same protein is involved in pain sensation [14]. In the past few years the research has been extended. Loss of Plexin-B2 interferes with normal learning and memory in the adult mouse brain [15]. The role of Plexin-B2 parallels and overlaps the role of Shank3. Both are used at excitatory synapses in the brain. Both are involved in pain pathways in the spinal cord. In humans, these two genes are very near each other on chromosome 22, so almost all people who have PMS from a deletion are missing both genes. We can speculate that these genes exacerbate the damaging influence of each other.

What makes Plexin-B2 especially interesting for PMS is that it affects the brain circuit essential for remembering danger. Specifically, loss of Plexin-B2 in mice interferes with “conditioned fear recall”. That is, the mice will learn to recognize a warning tone when the tone signals a brief foot shock, but 2 days later they have forgotten the meaning of the warning tone. The neurons involved fail to form adequate synapses 2 to 3 days after the training period [15]. These are some of the same synapses where Shank3 operates. When I read this I nearly fell off my chair. (You could say I was shocked.) If there is one thing that my son, David does poorly, it is learning about danger. It took years to explain to David what it means when something is (dangerously) hot. It took equally long to warn him about stepping over an obstacle or curb. We often suppose that our children do not have the same sensitivity to pain as most people. That may be true, but we also might be misled by their inability to incorporate painful or fearful experience into memory.


Larger deletions of chromosome 22 can disrupt the PHF21B gene. This blog is about genes that have a role both in development and adult function. I have already written a blog on how PHF21B is critical for normal brain development. Now there is new research showing that PHF21B regulates synapses during “social” learning [16]. Social learning in mice is when a mouse can distinguish between a new mouse and one that has visited the cage before. Not distinguishing between a familiar mouse and a stranger is a serious inability. The Phf21b protein normally triggers parts of the DNA to build a memory after spending time with a new animal. In animals missing about half of their Phf21b protein, the ability to remember a fellow mouse (“conspecific”) is disrupted. The circuitry that is disrupted involves the Shank proteins. Thus, PHF21B is another gene that is important for both development and adult function, and is intimately associated with SHANK3.


Another gene that has received recent attention is CCDC134. To be honest, I did not pay much attention to this gene until recently. The gene is lost only with the very largest deletions (> 9 Mb), so loss of this gene is rare. CCDC134 had long been suspected to be essential for normal brain development, but mice missing CCDC134 died before they were old enough for behavioral studies. This past year a group in China produced a mouse that was missing Ccdc134 protein only in the cerebellum of the brain [17]. The cerebellum is well known as a critical area for motor coordination. Making a custom knockout mouse did the trick. Mice missing only Ccdc134 and only from the cerebellum develop malformation of the cerebellar Purkinje and granule cells. Mice with these deficits had problems with grip strength, motor coordination and motor learning. If you know a PMS child with a very large deletion who has serious difficulties standing and walking, it could be largely because of this gene. Most people with PMS have problems with the cerebellum. There is evidence that loss of Shank3 impacts the cerebellum in mice [9], but that more prominent malformations occur with deletions in people [18]. Now we know the largest deletions likely add substantially to the problem.

It can get very cold in winter

Larger and larger deletions have greater and greater impact on people with PMS. Even people with interstitial deletions that do not disrupt SHANK3 can have PMS. The combined developmental and adult functions of missing PMS genes, and their overlap with the function of SHANK3 at the synapse, conspire to make larger PMS deletions more detrimental in multiple ways. This blog is about recent finding in 3 PMS genes. Previous blogs have discussed other genes that impact PMS. As science advances we will learn more.

My parents never lived in a warm climate. One December my mother came to visit me at school in Atlanta, GA.  It was an unexpected 80 degrees that day. She asked, “Is it always this warm?” I said, “Yes.” The truth was, a year prior Atlanta had been blanketed with an equally rare snowstorm. Everyone in Atlanta knows it is colder in the winter, even though there can be the rare warm day. At this point, it is quite clear that larger [terminal] deletions of 22q13 are more impactful than smaller deletions or SHANK3 variants. PMS is more impactful than many other neurodevelopmental disorders. There will always be exceptions, but we must fully understand the rule before we can explain the exceptions.


Papers referenced

1.            Levy, T., et al., Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium. Hum Mol Genet, 2022. 31(4): p. 625-637.

2.            Breen, M.S., et al., Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome. HGG Adv, 2023. 4(1): p. 100145.

3.            Schenkel, L.C., et al., DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome. Clin Epigenetics, 2021. 13(1): p. 2.

4.            Sarasua, S.M., et al., Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome. Hum Genet, 2014. 133(7): p. 847-59.

5.            Halbedl, S., et al., Shank3 is localized in axons and presynaptic specializations of developing hippocampal neurons and involved in the modulation of NMDA receptor levels at axon terminals. J Neurochem, 2016. 137(1): p. 26-32.

6.            Liu, X., et al., SHANK family on stem cell fate and development. Cell Death Dis, 2022. 13(10): p. 880.

7.            Pillerova, M., et al., Neuromotor Development in the Shank3 Mouse Model of Autism Spectrum Disorder. Brain Sci, 2022. 12(7).

8.            Panagiotakos, G. and S.P. Pasca, A matter of space and time: Emerging roles of disease-associated proteins in neural development. Neuron, 2022. 110(2): p. 195-208.

9.            Otazu, G.H., et al., Neurodevelopmental malformations of the cerebellum and neocortex in the Shank3 and Cntnap2 mouse models of autism. Neurosci Lett, 2021. 765: p. 136257.

10.          Mossa, A., et al., Developmental impaired Akt signaling in the Shank1 and Shank3 double knock-out mice. Mol Psychiatry, 2021. 26(6): p. 1928-1944.

11.          Deng, S., et al., Plexin-B2, but not Plexin-B1, critically modulates neuronal migration and patterning of the developing nervous system in vivo. J Neurosci, 2007. 27(23): p. 6333-47.

12.          Vodrazka, P., et al., The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. Eur J Neurosci, 2009. 30(7): p. 1193-208.

13.          Laht, P., et al., B-plexins control microtubule dynamics and dendrite morphology of hippocampal neurons. Exp Cell Res, 2014. 326(1): p. 174-84.

14.          Paldy, E., et al., Semaphorin 4C Plexin-B2 signaling in peripheral sensory neurons is pronociceptive in a model of inflammatory pain. Nat Commun, 2017. 8(1): p. 176.

15.          Simonetti, M., et al., The impact of Semaphorin 4C/Plexin-B2 signaling on fear memory via remodeling of neuronal and synaptic morphology. Mol Psychiatry, 2021. 26(4): p. 1376-1398.

16.          Chin, E.W., et al., The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity-related genes. JCI Insight, 2022. 7(14).

17.          Yin, S., et al., Ccdc134 deficiency impairs cerebellar development and motor coordination. Genes Brain Behav, 2021. 20(7): p. e12763.

18.          Aldinger, K.A., et al., Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion. Am J Med Genet A, 2013. 161A(1): p. 131-6.


What do we know about PMS genes?

16 Dec 2017 1 - small
Our children trust us to do the best for them

Originally posted 24 January 2018
Updated 20 April 2021
Available in Portuguese http://pmsbrasil.org.br/o-que-nos-sabemos-sobre-os-genes-pms/


In the previous blog we learned which Phelan McDermid syndrome (PMS) genes are most important. SHANK3 has often been touted as the gene that causes PMS, but SHANK3 rarely operates on its own and in some people has nothing to do with PMS (those with interstitial deletions). We learned that large studies of human populations identify 18 PMS genes that are impacted by “natural selection”. Loss of these genes are highly likely to cause problems, the problems that add up to PMS. The genes are:


The big question is, what do we know about these genes? That is, how might they be contributing to PMS? This blog is based on a paper that not only identified these genes, but also pulled together what is currently known about each. Although the paper describes each gene’s function in detail (for well-characterized genes), it also classifies genes into groups. Those groups are quite informative and help us understand why PMS has certain characteristics.

Genes that impact brain development

It is now very clear why PMS can occur with or without SHANK3. Of the 18 PMS genes that are likely to have a high impact on PMS, at least 7 impact brain development: SHANK3, MAPK8IP2, PLXNB2, BRD1, CELSR1, SULT4A1, TCF20.

MAPK8IP2 sits almost adjacent to SHANK3 and we have known for years that loss of MAPK8IP2 in mice interferes with brain function (see MAPK8IP2 (IB2) may explain the major problems with walking and hand use).

PLXNB2 regulates the growth of neurons, especially early in development. PMS is a neurodevelopmental disorder, so nothing could be more important than regulating neuron growth.

CELSR1 is also crucial for neurodevelopment. Neurons are exquisitely organized into nuclei in the deep structures of the brain and into very precise layering in the cortex. For example, pyramidal neurons of the cortex are located only in certain layers of the cortex, with the dendrites reaching upwards and the axon pointing down. The axon often winds its way towards the white matter. CELSR1 is important for orchestrating the orientation of neurons to assure proper organization.

BRD1 regulates hundreds of other genes during development. It is highly associated with schizophrenia, as well as PMS. PMS individuals with terminal deletions greater than 1 Mb are missing BRD1 and the loss of BRD1 impacts the entire genome (see https://pubmed.ncbi.nlm.nih.gov/33407854/).

SULT4A1 was recently shown to impact the mitochondria in the brain (see New science: SULT4A1, oxidative stress and mitochondria disorder). Mitochondria convert food into energy for cells. Dysfunction of mitochondria explains why deletions that disrupt SULT4A1 can have a severe impact on neurodevelopment and adult brain function.

TCF20 is a very important gene for brain function. It can cause intellectual disability and other problems on its own. It probably explains why very large deletions in PMS can be more devastating than smaller deletions (see TCF20 may explain why some big deletions are worse than others).

Genes associated with sleep

There are three genes that have close association with sleep or sleep disturbance. SHANK3 impacts sleep in some individuals with PMS, but PIM3 (see this paper) and PRR5 (see this paper) have been identified in studies that explore which genes regulate circadian rhythms (so called, “clock” genes).

Gene associated with lymphedema

CELSR1, the gene important for proper orientation of cells during neurodevelopment, is also associated with inherited lymphedema. Presumably CELSR1 influences cell orientation and the structure in the lymph system during development.

Genes that have unknown function

We must recognize that just because a gene has never been closely studied, that does not mean it is unimportant. In fact, one genomic study makes a convincing argument that genes of unknown function are just as important as the well-characterized genes. PMS has 7 genes likely to be important, yet not well-studied: TRABD, ZBED4, SMC1B, PHF21B, SCUBE1, SREBF2, and XRCC6. The first two genes, TRABD and ZBED4, are of very special concern. One copy of each gene is missing in over 95% of individuals with terminal deletions. It is imperative we find out what these genes are doing and how loss impacts PMS.


This study of PMS genes was a critical step forward in understanding PMS. It provided a short list of culprits. It explains why interstitial deletions cause PMS and it identifies where our research efforts need to be focused. Most importantly, it provides new targets for therapeutics. Unfortunately, a lot of time has gone by without any serious effort to encourage research into the full array of PMS genes. The genes listed above warrant much more study. As a parent of a child with PMS, I strongly feel we should make an effort to encourage the scientists who study these genes. It is hard to understand why so many important genes of PMS are being ignored by the PMS community.


Previous blogs

Which PMS genes are most important?
Are children with Phelan McDermid syndrome insensitive to pain?
Looking for Opportunities
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
Science Leadership
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