The PMS Diagnosis Gap: Why Many Children Go Undetected and Face Delays in Diagnosis
New findings suggest that Phelan-McDermid Syndrome is nearly twice as common as previously thought — and the reason comes down to a critical flaw in how genetic testing has long been conducted.
The recent CureSHANK Drug Development Symposium made one thing clear: much more work is needed to ensure that every individual affected by Phelan-McDermid Syndrome (PMS) receives a genetic diagnosis confirming their condition. A forthcoming publication by the Seaver Autism Center, New York and CureSHANK suggests that the number of people living with PMS — known as prevalence — has long been underestimated and may in reality be up to twice as high as current figures indicate.
Why is true prevalence being underestimated?
There is no scientific evidence that PMS has become more common. The problem is that certain genetic diagnostic tests — some of which are still in use today — have been missing individuals with PMS due to flaws in their design.
What are the different genetic classes of PMS?
To understand the issue, it helps to first look at the different genetic forms of PMS. The condition was originally linked to a missing segment at the end of chromosome 22. As genetic methods advanced, researchers identified SHANK3 — a gene located at the very tip of that segment — as the cause for PMS. Later, whole genome sequencing revealed that small mutations within SHANK3 itself could also cause the condition, not just large chromosome deletions.
Today, the genetic causes of PMS fall into four categories:
Class I deletions — affect part or all of the SHANK3 gene
Class II deletions — affect all of SHANK3 and several neighboring genes on chromosome 22
SHANK3 mutations — very small deletions, duplications, or sequence changes within the SHANK3 gene itself
Other rare rearrangements of the relevant region of chromosome 22
In every pathogenic case, the result is a significant reduction in functional SHANK3 protein in cells. Because so many different types of genetic changes have been reported in people with PMS, it is often unclear whether partial SHANK3 protein fragments are still being produced — and if so, what role they might play in shaping symptoms.
How is PMS genetically diagnosed?
Whole genome sequencing (WGS) is the gold standard for diagnosing neurodevelopmental disorders, as recommended by both the American College of Medical Genetics and Genomics and the American Academy of Pediatrics. A forthcoming publication, presented at the Symposium, confirmed that WGS is the most reliable method for detecting all genetic changes that can cause PMS. Other approaches — including exome sequencing and older gene array tests — can miss mutations entirely. Gene arrays also yield only a coarse picture of Class I and Class II deletions, limiting our ability to draw meaningful connections between a person's specific genetic change, their symptoms, and their medical history.
What needs to be done?
Sequencing technologies have grown dramatically more reliable and affordable in recent years, with a $100 genome now within reach. WGS may soon be the most cost-effective diagnostic option available. Healthcare providers should therefore make WGS their standard test for suspected PMS. Equally important, genetic testing companies must update their technologies to deliver accurate results and stop missing a significant proportion of PMS cases.
Why does accurate genetic testing matter?
There are three compelling reasons. First, an accurate PMS diagnosis is essential for individuals to receive the best possible care and to qualify for insurance coverage. No one should be left with an undiagnosed neurodevelopmental disease because a testing company is relying on outdated technology. Second, pharmaceutical and biotech companies routinely use prevalence data when deciding whether to invest in developing treatments for a given condition. Accurate figures are therefore critical to ensuring that PMS is properly evaluated as an attractive commercial opportunity. Third, researchers need a precise picture of the full genetic landscape of PMS to design effective new therapies, select appropriate laboratory models, and structure clinical trials correctly.
Ralf Schmid is the Chief Scientific Officer at CureSHANK. He can be reached at research@cureshank.org.