Originally created 12 September 2020
Updated 31 January 2022
I am going to describe four types of Phelan-McDermid syndrome (PMS). By type, I mean four different genetic arrangements that can result in PMS. These are technically called “genotypes”. The four genotypes do not address the mechanisms that create each genotype. For example, my son, David, has Type 1 (Genotype 1) from an unbalanced translocation, but others have PMS Type 1 from de novo deletions or ring chromosomes. The types can be used by parents as a very simple short-hand to share information about their child.
Phelan McDermid syndrome Type 1, terminal microdeletion
This is the original 22q13.3 microdeletion syndrome described by Katy Phelan and Heather McDermid. It is also the most common type among people identified with PMS.
A microdeletion occurs when multiple genes on a chromosome are removed. Most microdeletions are too small to see under a microscope, but Katy Phelan has described some microdeletions that are large enough to be visible. Deletion sizes range from about 0.2 Mb to 9.3 Mb, with an average of 4.5 Mb. Nearly all of the microdeletions observed are terminal deletions (continue to the end of the chromosome). Terminal deletions much smaller than 0.2 Mb do not include SHANK3 and do not produce a syndrome.
Phelan McDermid syndrome Type 2, interstitial microdeletion
An interstitial microdeletion is a deletion that removes multiple genes, but does not extend to the end of the chromosome. For PMS Type 2, the deletion does not reach SHANK3, which is near the end of the chromosome.
Interstitial deletions that produce PMS, but do not disrupt SHANK3 are relatively rare. Some scientist have argued against including them in the definition of PMS. However, a recent scientific consensus paper (https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02180-5) justifies the strong reasoning for including Type 2 in the definition of PMS.
Phelan McDermid syndrome Type 3, single SHANK3 rare variant
A rare variant is an atypical version of a single gene. PMS caused by a rare variant of SHANK3 is called Type 3. Sometimes this has been called a “mutation” of SHANK3. That terminology is not always technically correct, so “variant” is preferred.
Type 3 is currently the second-most common example of PMS. However, rare variants of SHANK3 have been found in large collections of DNA from people with autism spectrum disorder (ASD). Although only 1 to 2% of people with ASD might have a rare variant of SHANK3, this still a potentially large population of people who might have PMS Type 3. More research is needed.
Phelan McDermid syndrome Type 4, heterozygous deleterious variants
You child does not have PMS Type 4. PMS Type 4 is included here for completeness. Individuals can inherit two copies of unusual variants of SHANK3, one from each parent. This can produce PMS as a recessive disorder. There may be cases of Type 4, but they would be very rare, indeed.
The consensus paper (see the link, above) has provided a clear statement about how the PMS diagnosis should be applied. This is the classification that geneticists and scientist should use.
- PMS-SHANK3 related (Types 1, 3, 4)
- PMS-SHANK3 unrelated (Type 2)
Note that most cases of PMS fit one of the four PMS types. However, the reality of genetics is that some cases can be very messy. The four genotypes of PMS are not always clearly segregated in any given individual. An individual can have an interstitial deletion, yet also have a pathological variant of SHANK3. This could be described as both PMS Type 2 and PMS Type 3. The classification system from the consensus group, PMS-SHANK3 related versus PMS-SHANK3 unrelated,covers all possible cases without any overlap.
Sometimes two different genotypes are actually very similar
Most PMS Type 1 and PMS Type 3 cases are very different from each other. An individual with a large terminal deletion is likely to have problems not shared by an individual with a SHANK3 variant. With Type 1 there are many important genes involved, some known to produce profound effects. In Type 2, any effect would only result from disturbing SHANK3. Yet, someone with a small terminal deletion (PMS Type 1) might be very similar to someone else with PMS Type 3. Although in different categories, they could end up being very similar.
PMS is a syndrome
PMS is defined by its genetics. However, central to all syndromes is that the individual must have a phenotype reflecting the syndrome. There are some individuals with interstitial deletions and other individuals with with SHANK3 variants who simply do not have significant features of Phelan-McDermid syndrome. These are very interesting cases, but they cannot be called PMS.
This simple system of PMS Types 1 to 4 can help parents quickly share the basic genetics of their children. PMS Types 1 and 2 have a deletion size associated with them. PMS Type 3 does not. Some manifestations of PMS, like lymphedema are not seen with Type 3. Sharing your child’s PMS Type can be an ice breaker during introductions and help a parent share key information without having to be a genetics expert.
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