Does SHANK3 cause Autism?

David shows you don’t need to have autism to promote autism awareness.

Originally posted 18 March 2018
Updated 23 July 2021
Updated 9 April 2024
Available in Portuguese http://pmsbrasil.org.br/shank3-causa-autismo/

Phelan McDermid syndrome (22q13 deletion syndrome or PMS) is often equated with autism spectrum disorder (ASD). The exact definition of PMS was somewhat murky for many years. A consensus paper and the establishment of an ICD-10-CM code for PMS (Q93.52) has led to improved clarity (see Defining Phelan McDermid syndrome). Yet, there are still disagreements among families, scientists and clinicians. Expanded availability of genetic testing has emphasized an old question: does it make sense to diagnose someone with PMS when there are few symptoms? How few? How severe? The question arose originally in regard to people with interstitial deletions (technically, PMS-SHANK3 unrelated). Now it has resurfaced in individuals with SHANK3 variants of unknown significance. Diagnosis is an important sticking point for parents trying to get services for their child. Some clinical geneticists are good about reading the latest scientific literature and seeking advice. Others seem to make definitive statements about a child that are not consistent with broad consensus. Professionals are caught in the uncertainty of diagnosis. As a parent, I only wish some would skip the part about being certain and admit to the limitations of the field. My family fell victim to a geneticist whose certainty was unfounded, with tragic consequences. The limits of scientific understanding should encourage humility in practitioners.

For a long time, the relationship between PMS and ASD was also murky. Some studies reported that up to 70% of the PMS patient population had an ASD diagnosis; other studies reported numbers as low as 30%. Many parents admit they have received a somewhat arbitrary ASD diagnosis from clinicians to help their child receive services. One scientific study that looked closely at the symptoms of PMS patients argued the behaviors are not really ASD. Another study showed the ASD diagnosis is unreliable in children with both intellectual disabilities and movement problems. Two studies suggested the number of cases with ASD depends on the sizes of the chromosomal deletion in the population. No wonder there was so much confusion regarding the incidence of ASD among PMS patients. Over time, more and more careful studies were conducted on individuals with PMS. It is clear now that the overlap between PMS and ASD is large. The actual number may be higher than 80%.

There is a misconception among many parents that a case of PMS that involves the SHANK3 gene must lead to ASD, since “SHANK3 is an autism gene”. For the record, there are no “autism genes”, only autism-associated genes. SFARI (Simons Foundation Autism Research Initiative) is one organization that tracks genes associated with ASD in their SFARI Gene database. There are currently about 800 autism-associated genes categorized in the database. SHANK3 is a category 1 gene, meaning that the association with autism is high. What does that mean?

Most genes of the human genome come in slightly different flavors. Each flavor is called a “variant”. The SFARI database tracks rare variants that can strongly contribute to autism. That is, the most common versions of the SHANK3 found in the general population does its job without any problem. What sometimes happens in PMS is that the parents have common versions of SHANK3, but the child has a copy of SHANK3 that is significantly different from her parents. If the child has a resulting disorder, the changed gene is called a “deleterious de novo” event. In this context, deleterious means damaging and de novo means new, since the parents have the more common variants of the gene. A deleterious de novo event might be a partial chromosome deletion (like 22q13 deletion) or a gene mutation (as in our SHANK3 example). It is no mystery why rare deleterious gene variants are rare. They are rare because people with a serious genetic problem do not tend to have children of their own.

The SFARI gene database is mostly concerned with rare variants. However, common variants can also contribute to a disorder. In fact, in ASD most cases are a result of common variants. Let me explain how common variants and rare variants contribute to a disorder using a metaphor. Let’s say you are on a whale-watching boat filled with lots of people. Today is unusual, the normally calm waters have large waves. This is a rare event. On choppy seas the waves in the water can make the boat rock back and forth. The water is rough and that is associated with a risk of capsizing. With a seaworthy vessel the passengers are in no immediate danger. Of course, a single person walking from one side of the boat to the other side has no noticeable influence on the boat. However, if too many people move to one side of the boat a large wave might capsize the boat and send everyone into the water. This is a combination of a high risk rare event (choppy seas) and many small contributions all in one direction (too many people on one side). The combination can lead to disaster.

Like the people on the boat, most variants are quite common and contribute only a tiny bit on their own. These variants are very common in people. But, if you have too many common variants on the autism side of the boat, you have a major risk of developing autism. An autism-associated gene is rare and can strongly contribute to autism. Like choppy seas, a single autism-associated gene can greatly raise the risk of autism. The combination of a deleterious variant of an autism-associated gene, plus enough common variants in one direction (towards autism), can pass the tipping point and produce a case of autism.

To be clear, everyone has variants in their genome. Too many variants of certain genes can raise the risk of specific disorders, from diabetes to heart disease. Judging the risk of a disorder from a person’s common variants is called polygenic risk and is measured using polygenic risk scores.

What about PMS?  PMS occurs primarily by either a partial (“terminal”) deletion of chromosome 22, or a pathogenic variant of SHANK3. Terminal deletions often includes multiple important genes, like SHANK3, BRD1, CELSR1, and SULT4A1, each associated with intellectual disability or other neurodevelopmental disorder. SHANK3 is most commonly affected because it sits near the end of the chromosome where breaks occur most often. In addition, SHANK3 is a large gene that can have a substantial impact if disrupted by a deleterious de novo event.

I have explained that there are two categories of genes that can contribute to autism. There are common variants that, together, can add to the risk of autism. The other type of gene variant, one that may arise from a deleterious de novo event, is rare and makes a large contribution to autism risk. Some SHANK3 variants are common and occur throughout the population. Some rare variants greatly raise the risk of autism. In PMS, it is the combined risk of too many common variants on one side of the ship, plus a deleterious de novo event (often from a deletion), that can send a child tumbling into ASD.

In general, most people with autism (about 70%) do not have a rare variant of an autism-associated gene. Their autism results from many common variants that have combined with developmental and environmental factors to produce autism. In a child with both PMS and ASD, the combined impact of common variants plus a de novo events (chromosomal deletion or pathogenic SHANK3 variant) leads to ASD. In other children with PMS, less often, the genetic change on chromosome 22 combined with the common variants of the child may not add up to ASD.

arm22q13

Some previous blogs

We need to study interstitial deletions to cure PMS
What do we know about PMS genes?
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
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
22q13 deletion syndrome – an introduction