Which are the causes of 22q13 deletion / Phelan-McDermid Syndrome?

TL;DR: Phelan-McDermid syndrome (also known as 22q13 deletion syndrome) is caused by the loss of genetic material at the end of the long arm of chromosome 22, most notably affecting the SHANK3 gene. This deletion prevents the body from producing enough of the SHANK3 protein, which is essential for the healthy development and function of connections between brain cells.

What causes Phelan-McDermid syndrome?

The primary cause of Phelan-McDermid syndrome is a genetic abnormality involving the terminal end of chromosome 22. In most cases, this involves a deletion of the 22q13.3 region. Think of your DNA as a complex instruction manual for building a human; in Phelan-McDermid syndrome, a specific "page" or "chapter" at the very end of chromosome 22 is missing. The most critical component of this missing material is the SHANK3 gene. When this gene is absent or damaged, the brain does not receive the proper instructions to build the "scaffolding" required for neurons to communicate effectively, leading to the developmental and neurological symptoms associated with the condition.

Is Phelan-McDermid syndrome hereditary?

In the vast majority of cases, Phelan-McDermid syndrome occurs as a "de novo" event, meaning it happens spontaneously in the egg or sperm cell or during early embryonic development. It is not typically inherited from a parent. However, in a small percentage of cases (approximately 15-20%), a parent may carry a balanced chromosomal rearrangement, such as a translocation, where pieces of chromosomes have swapped places. While the parent is healthy because they have all their genetic information, they can pass on an unbalanced version to their child, leading to 22q13 deletion. Clinical geneticists recommend parental chromosomal analysis to determine if the deletion is sporadic or familial.

Are there environmental or external triggers?

There are no known environmental, dietary, or behavioral triggers for Phelan-McDermid syndrome. Because the condition is strictly genetic—arising from a physical absence of DNA—it cannot be caused by anything a parent did or did not do during pregnancy. It is not linked to autoimmune, infectious, or metabolic processes; rather, it is a structural chromosomal difference present from the moment of conception.

How do geneticists classify the specific causes?

The genetic underlying causes of Phelan-McDermid syndrome can be categorized into three primary types:

• Terminal Deletions: The most common form, where the very tip of the 22q chromosome is missing.


• Interstitial Deletions: A piece is missing from the middle of the 22q13 region, which may or may not include the SHANK3 gene.


• Ring Chromosome 22: The chromosome forms a circle and loses genetic material from both ends.


• SHANK3 Point Mutations: A small change within the gene itself that renders it non-functional, even if the chromosome structure appears intact.

What does current research tell us?

Research into Phelan-McDermid syndrome is shifting from merely identifying the deletion to understanding how SHANK3 protein deficiency affects synaptic plasticity. Scientists are currently using "organoids" (mini-brains grown in a lab) and animal models to test how restoring SHANK3 function might improve communication between neurons. With 35 members on DiseaseMaps.org sharing their lived experiences, the collective data from the patient community continues to help researchers correlate specific deletion sizes with varying clinical outcomes.

Next steps

• Consult with a clinical geneticist to review microarray results and determine if parental testing is necessary.


• Connect with the Phelan-McDermid Syndrome Foundation for resources on the latest clinical trials and research updates.


• Join the 35 community members on DiseaseMaps.org to share experiences and learn from others managing this condition.


• Discuss neurological support with a pediatric neurologist to manage symptoms related to SHANK3 deficiency.

Medical disclaimer: This information is for educational purposes and does not replace professional medical advice, diagnosis, or treatment; always seek the advice of your physician or other qualified health provider with any questions regarding a medical condition.

References

• NIH Genetic and Rare Diseases Information Center (GARD): Phelan-McDermid syndrome.


• Orphanet: 22q13.3 deletion syndrome (ORPHA:73248).


• OMIM (Online Mendelian Inheritance in Man): Phelan-McDermid Syndrome; PHMDS (#606232).


• Phelan-McDermid Syndrome Foundation (pmsf.org).