While SHANK3 has been identified as a major contributor to intellectual disability and autism spectrum disorder, there has always been a lingering question of why people with Phelan McDermid syndrome (PMS) have very similar symptoms (phenotype) whether or not SHANK3 is impacted. That is, people with terminal deletions that remove SHANK3 are not very different from people with so-called “interstitial deletions”. This observation is the main reason why the current definition of PMS says that SHANK3 is usually, but not always, impacted (see The 22q13.3 Deletion Syndrome).
I have written several blogs that cover the evidence, so far, why intellectual disability and autism are not limited to one gene of 22q13 (see PMS for Dummies, Which PMS genes are most associated with Autism? Which PMS genes are most important?). In this blog we look at new data indicating that 22q13 has more autism-associated genes than we previously knew.
What we knew before
Genes with a high “pLI” (genes that are very rarely mutated in the general population) are associated with intellectual disability. For 22q13 they are: SHANK3, MAPK8IP2, PLXNB2, TRABD, PIM3, ZBED4, BRD1, TBC1D22A, GRAMD4, CELSR1, SMC1B, PHF21B, PRR5, SULT4A1, SCUBE1, TCF20, SREBF2, and XRCC6. Most, if not all of these genes contribute to intellectual disability, although some are more certain. While 18 genes may seem like a lot of genes, remember that PMS can delete up to 108 genes. Still, it is impressive that nearly 17% of the genes of 22q13 potentially contribute to intellectual disability. The high number of these high pLI genes explains why intellectual disability is generally more severe with larger deletions, and it explains why interstitial deletions can also produce moderate to severe intellectual disability. But, what about autism spectrum disorder (ASD)? The frequency of ASD in PMS is an area of debate, various studies report anywhere from under 30% to over 70% incidence of ASD. The natural history study of PMS should narrow this range. Regardless, ASD is a component of the PMS population.
So far, three genes of 22q13 have been clearly associated with ASD: SHANK3, MAPK8IP2 and SULT4A1. It is probably no accident that these three genes also show up as high pLI genes.
What is new
Two new lines of research have identified new candidate ASD genes on 22q13. One candidate gene has arisen from studies of epigenetics, the regulation of genes. Genes occupy only about 1% of the DNA. Much of the remaining DNA is dedicated to controlling when and how often a specific gene is put to work. Gene regulation is essential for successful development of the brain (and all other body parts) and for responding to changes in the environment. By environment we can refer to the external environment (e.g., adapting to colder weather) or we can be concerned with the internal environment of the body (e.g., building muscle with increased exercise). There is earlier data suggesting a weak contribution of the gene BRD1 to ASD (see Which genes cause brain abnormalities in Phelan McDermid syndrome?). However, epigenetic studies have reinforced the connection between BRD1 and ASD (see Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders). So, BRD1 can be considered an autism-associated gene.
Perhaps more exciting is the latest work on “second hits”. Second hits are when one gene is lost or damaged, and then the remaining copy of the gene is also affected. Second hits matter because some genes can operate just fine with only one copy. We have two copies of most genes in our DNA, one from each parent. When a person has a chromosomal deletion, which is what happens in over 95% of the cases of PMS, that leaves the person with only one copy of those genes. A second hit is when the remaining copy has a mutation, or even just an dysfunctional variant inherited from one parent. What do we know about second hits? A new paper has identified up to 4 genes of 22q13 that may contribute to ASD, given a second hit (see Recessive gene disruptions in autism spectrum disorder). One PMS gene stands out, KIAA0930 and three others are additional candidates, CHKB, ARFGAP3, and ZBED4.
This rounds-out the current full list of 8 ASD-associated genes: SHANK3, MAPK8IP2, CHKB, ZBED4, BRD1, KIAA0930, SULT4A1, and ARFGAP3.
PMS is most often a terminal deletion of 22q13. A deletion of the chromosome that includes SHANK3 is the most common deletion, but sometimes a deletion does not disrupt that gene. Interstitial deletions can disrupt up to 17 other genes likely to contribute to the moderate to severe intellectual disability that characterizes PMS. Infrequently, a second hit on one or more of 7 genes in the interstitial region of 22q13 may also contribute to autism spectrum disorder. In the overwhelming cases of PMS (called terminal deletions), many genes contribute to intellectual disability and, if autism spectrum disorder is part of the clinical picture, SHANK3 and one or two other genes may also be contributing to that aspect of the disorder.
Some selected earlier blogs
PMS for Dummies
Which genes cause brain abnormalities in Phelan McDermid syndrome?
PMS, IQ and why interstitial deletions matter
MAPK8IP2 (IB2) may explain the major problems with walking and hand use
TCF20 may explain why some big deletions are worse than others
Current trends in SHANK3 research
Which PMS genes are most associated with Autism?
Does SHANK3 cause Autism?
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?
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?
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