Potential Blood-Based Biomarkers of Phelan-McDermid Syndrome
By: Meagan Hutchinson, PMSF Scientific Program Coordinator and Lauren Schmitt, PhD, PMSF Chief Science Officer
Date: September 2, 2026
Phelan-McDermid syndrome is caused by either a deletion involving the end of the long arm of chromosome 22, in a region called 22q13, typically including SHANK3, or by a genetic change or variant in a gene called SHANK3. The SHANK3 gene plays an important role in how brain cells communicate with one another.
Individuals with Phelan-McDermid syndrome can have very different clinical symptoms and experience different levels of severity of symptoms. In addition, the size of the chromosome 22 deletion can vary widely among people with Phelan-McDermid syndrome. For individuals with deletions, differences in symptoms may be, in part, explained by the size of the deletion since the loss of other genes in the region also can impact brain and body development and function.
In general, larger deletions often are associated with a greater number of medical concerns and more severe symptoms. Larger deletions have been linked to more severe developmental delays as well as low muscle tone, called “hypotonia”, in newborns. They also have been associated with higher rates of growth and physical features, seizures, challenges with everyday skills, kidney abnormalities, lymphedema, heart defects, brain differences seen on imaging, and recurrent infections.
What Did the Study Do?
In a recent study, Dr. Antonio Persico’s team at the University of Modena and Reggio Emilia in Italy explored whether deletion size can influence symptoms in Phelan-McDermid syndrome.
The researchers studied 63 people with Phelan-McDermid syndrome to better understand whether the size of a chromosome 22 deletion is related to differences in symptoms using detailed clinical evaluations and genetic testing results. The researchers also looked at whether specific additional genes may contribute to specific clinical features of Phelan-McDermid syndrome.
What Did the Study Find?
This study found that deletion size was associated with several important features of Phelan-McDermid syndrome. They found that larger deletions were linked to:
- More severe deficits in expressive language (i.e., how person communicates what they want, think, or feel)
- Greater delays in motor development
- More severe deficits in gait and muscle strength
- More severe deficits in social communication skills (e.g., making eye contact, using gestures, or sharing attention with another person around an object or activity)
- Higher likelihood of certain infections associated with the onset of behavioral changes
- Higher likelihood of structural differences in the brain seen on MRI
- Higher likelihood of differences in physical features (e.g., dysmorphisms)
- Higher likelihood of kidney and urinary tract abnormalities
- Higher likelihood of bipolar disorder
The researchers identified several candidate genes that might contribute to some of these features. Several of these candidate genes are involved in brain development and nervous system function, while others are involved in the development of other parts of the body.
What Are the Limitations?
This study only included 63 people, which is a relatively small number for studying a condition as heterogeneous (e.g., highly clinically variable) as Phelan-McDermid syndrome. The study looked for statistical relationships between deletion size and clinical features, thus these relationships do not prove that a particular deletion size or gene directly causes a specific feature. Many genes may work together along with many other factors, including a person’s overall genetic background and environmental influences, which also affect how Phelan-McDermid syndrome presents.
Therefore, future studies are needed to determine whether the candidate genes truly contribute to specific features of Phelan-McDermid syndrome.
What Does This Mean and What’s Next?
Overall, this study helps our understanding of why people with Phelan-McDermid syndrome can have very different symptoms and levels of support needs. For example, larger chromosome 22 deletions may include additional genes that contribute to unique differences in development, communication, movement, behavior, and medical conditions. Importantly, these findings suggest that SHANK3 is not the only gene that may influence the features of Phelan-McDermid syndrome. In other words, when a chromosome 22 deletion includes additional genes beyond SHANK3, the loss of those genes may contribute to differences in a person’s symptoms and medical needs.
For families, this study does not indicate any immediate change in medical care since findings must be replicated to link specific additional genes to clinical features. For individuals with deletions including the ARSA and/or MLC1 genes, please review the Medical Advisory on the rare conditions associated with these genes that have been previously described. Families should always reach out to their medical team for specific questions. Additionally, families may be interested in utilizing our Genetic Counseling Support Program with Tess Levy.