SHANK3 is a gene that is important for the development and function of the nervous system. Genes are like instruction manuals in our bodies that help cells grow and work. SHANK3 is one such gene that tells our bodies how to make a protein also called SHANK3. Proteins carry out many of the essential functions in our cells. 

The SHANK3 protein helps nerve cells, or neurons, talk to each other.  This communication is needed for many brain functions, such as learning, memory, and social interactions. It is also needed for the signals the brain sends to the rest of the body, for functions like walking.

How does SHANK3 do this? It can be thought of as a support structure. It provides the structure necessary for neurons to receive signals.

SHANK3 variants versus deletions

In Phelan-McDermid syndrome, most people have a problem with their DNA called a deletion. This means that a piece of the DNA, which usually includes the SHANK3 gene and other genes, is missing. But some people with Phelan-McDermid syndrome have a different kind of problem called a SHANK3 variant. This means that there are changes in the DNA within the SHANK3 gene itself. 

Because SHANK3 is so important in the nervous system, these variants can be enough to cause Phelan-McDermid syndrome.

What exactly is a SHANK3 variant?

A gene variant occurs when there are changes to a typical DNA structure of a gene. The type of change will impact how much the gene is affected. If the gene is thought of as an instruction manual made up of letters and words, exchanging one letter for a similar letter may not make much of a difference and can be read the same way.  Exchanging letters or words for very different letters/words can change the meaning of the instructions. Some changes could cause the instructions to stop all-together. These changes could mean that the SHANK3 protein would not function properly, or may not be made at all. Below are some examples of common variant types:

Example variant type	SHANK3 DNA sequence	Effect on SHANK3 protein
No variant	The ball rolled down the hill.	Functional protein
Missense variant – a letter is exchanged	The ball rolled down the hilk.	Likely functional protein, the change did not have a big impact and the instructions can likely still be understood
Missense variant – a letter is exchanged	The ball rolled down the sill.	Function of the protein is changed and there is a new meaning, could cause dysfunction
Nonsense variant – causes instructions to stop short	The ball ___________	Likely dysfunctional protein
Duplication – a part of the gene sequence is repeated	The ball rolled rolled down the hill.	Likely still functional protein, instructions can likely still be read as intended
Deletion (in part of the gene)	The ball ______ down the hill.	Likely dysfunctional protein
Bigger deletion (of multiple genes including SHANK3)	____________	Copy of gene fully lost – no instructions for the protein

There are many different types of variants that can happen anywhere along a gene sequence. Due to the many possibilities, each variant is carefully analyzed by genetics experts in order to make a call of whether it causes Phelan-McDermid syndrome. This analysis occurs during genetic testing and is the process for getting a diagnosis.

What do the labels of SHANK3 variants mean?

Genetics experts use labels to classify different types of variants based on how likely they are to cause disease.

1. 1. Pathogenic variant: This is a change in the gene that is known to cause a disease. To be considered pathogenic, the variant has to have a significant impact on the instructions for making the protein (as explained before). Additionally, there should be evidence that people with this variant have shown symptoms of the disease. Experts examine cases where the same variant has been found in people diagnosed with the disease and displaying obvious symptoms. So, it’s a strong indicator that the variant is responsible for causing the disease.

2. 2. Likely pathogenic variant: Sometimes, a variant may have the potential to affect the protein’s function but there might not be enough data to confirm if it is directly connected to causing a disease. In such cases, the variant is classified as “likely pathogenic.” It means there is a higher chance that it could cause dysfunction in the protein, but more evidence and data are needed to be certain.

3. 3. Variants of uncertain significance (VUS): When a variant is rare or there isn’t enough information available to determine its impact, it is classified as a VUS. This means that the significance of the variant is not certain. Ongoing research and data collection are needed to better understand these variants and their association with diseases.

It is important to note that as more data is collected and research progresses, the classification of variants may change over time. Generally, only individuals who have a pathogenic variant will receive a diagnosis of the associated disease. 

How are SHANK3 variants detected?

Because SHANK3 variants happen to a very small area of the DNA (one gene), sensitive tests are needed to find them. These tests are called “sequencing” tests which read the DNA letter by letter. These tests provide a lot of information. This test could read all genes (whole genome sequencing), or just genes that make proteins (whole exome sequencing). Other tests may not be sensitive enough to pick up a SHANK3 variant, but could pick up a larger deletion of DNA.

Are SHANK3 variants inherited?

Most variants in the SHANK3 gene happen randomly, occurring before a person is born. These random variants are called “de novo” in genetic reports. They can happen in the sperm or egg prior to fertilization. These errors are not considered anyone’s fault. Errors happen to DNA frequently, to many genes. Unfortunately, errors that impact SHANK3 can have a bigger impact than many other random errors. 

There is a very small percentage of cases where a SHANK3 variant may be inherited from a parent.  For example, a parent might have a genetic variant in only some of their cells, such as the sperm cells that create an embryo. This is called “mosaicism” in the parent. These types of SHANK3 variants are rare and cannot be seen from sampling blood. Further tests are needed in these cases. There is also a very small possibility that a SHANK3 variant causes large impacts in a child and is inherited from a parent who is only mildly impacted. This possibility is an area of ongoing research. 

Current research data suggests that the majority of variants in the SHANK3 gene that cause Phelan-McDermid syndrome are not inherited. 

In contrast, for deletions that cause Phelan-McDermid syndrome, around 80% are believed to happen randomly, while roughly 20% are thought to be inherited from a parent. 

Do deletions impact SHANK3?

Many people with Phelan-McDermid syndrome have deletions in their DNA that affect more than one gene. The majority of these deletions include the SHANK3 gene. As a result, most people diagnosed with Phelan-McDermid syndrome have some kind of disruption to the SHANK3 gene. This disruption could occur through either a deletion or a variant in the SHANK3 gene alone. 

A small number of people diagnosed with Phelan-McDermid syndrome may have a deletion which does not involve the SHANK3 gene. Researchers are actively studying the impacts of these specific deletions and comparing them to the ones that do include the SHANK3 gene. This ongoing research aims to better understand the effects of these different types of deletions. If you’re interested in learning more about this topic, read a publication by the Phelan-McDermid Syndrome Foundation’s Scientific Advisory Committee at the following link: https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02180-5

What does SHANK3 haploinsufficiency mean?

It’s important to understand this term because it is sometimes used to define Phelan-McDermid syndrome. It may also be a requirement for participating in clinical studies.

Haploinsufficiency is a term that describes a situation where a person has only one working copy of a gene instead of the usual two. In our bodies, we have 23 pairs of chromosomes, and each chromosome contains specific genes. This means we normally have two copies of each gene, one on each chromosome of the pair.

Haploinsufficiency happens when one of the gene copies doesn’t work properly or is missing altogether. This means that the person has only one working copy of the gene instead of the usual two. As a result, the gene is not able to produce enough of the protein it is supposed to make in order to carry out its job effectively.

In the case of Phelan-McDermid syndrome, as discussed earlier, the majority of people with this condition have SHANK3 haploinsufficiency. This means they either have a deletion that removes one copy of the SHANK3 gene, leaving only one healthy copy, or they have a variant in SHANK3 that disrupts one copy, again leaving only one healthy copy. So, for most individuals with Phelan-McDermid syndrome, the term SHANK3 haploinsufficiency applies because they have only one working copy of the SHANK3 gene. Scientists sometimes use this term interchangeably with Phelan-McDermid syndrome.

For more details on haploinsufficiency – read this blog by Phelan-McDermid syndrome dad and scientist, Dr. Andrew Mitz at the following link: https://arm22q13.wordpress.com/2022/09/20/shank3-haploinsufficiency-and-gene-therapy/

Is SHANK3 the whole story? Or do other genes matter?

While disruption of SHANK3 alone is important and can cause many symptoms of Phelan-McDermid syndrome, it is not the only factor involved. Other genes affected in deletions also play a role. Research studies have found that people with larger deletions affecting more genes tend to experience more complex medical issues. These larger deletions may have a greater impact on language, developmental milestones, and intellectual disability. Some symptoms, such as kidney issues, are typically not seen unless there is a deletion involving multiple genes. This all suggests that other genes contribute to the symptoms and characteristics of the syndrome.

Can you explain the drugs being developed to target SHANK3?

Scientists are exploring new technologies to address the loss of SHANK3 function. One approach is gene replacement therapy, where a healthy copy of the SHANK3 gene is introduced to make up for the missing or non-working copy in Phelan-McDermid syndrome. 

Another approach is RNA therapy, which aims to increase the amount of healthy instructions for making the SHANK3 protein.

These therapies are exciting because they target the underlying cause of the symptoms, rather than just managing the symptoms themselves. However, there are still many unanswered questions. Scientists are working on understanding the safety of these therapies, how to deliver the drugs effectively, the appropriate dosage, and the optimal timing for treatment. They are also investigating whether these therapies can be beneficial for individuals with deletions of multiple genes and whether the age at which treatment is given makes a difference.

To find answers to these questions, researchers are conducting experiments using animal models. They need to gather enough evidence before these therapies can be tested in clinical trials involving humans. This process takes time, but the Phelan-McDermid Syndrome Foundation (PMSF) will keep everyone updated on the progress being made in this field.

To learn more about these drugs being developed, check out:

Explanation of RNA therapy: https://www.youtube.com/watch?v=zgMIatQjvI0

Podcast on an RNA therapy for Phelan-McDermid syndrome: https://podcasts.apple.com/us/podcast/dr-sue-fletcher-and-dr-rebecca-simmons-development/id1666661206?i=1000605277056

Explanation of gene therapy: https://www.youtube.com/watch?v=clI6QYl-8S4

Podcast on a gene therapy for Phelan-McDermid syndrome: https://podcasts.apple.com/us/podcast/jaguar-gene-therapy-a-gene-therapy-for-phelan/id1666661206?i=1000621959401