What is Phelan-McDiarmid syndrome?

Phelan-McDiarmid syndrome is a rare genetic disorder caused by deletions or mutations associated with the SHANK3 gene on chromosome 22. These genetic changes can lead to a wide range of medical, intellectual and behavioral challenges.

Most people with Phelan-McDiarmid syndrome also meet the criteria for autism spectrum disorder. Changes affecting SHANK3 are thought to account for up to 1% of autism spectrum disorder cases.

Genetic data suggests Phelan-McDiarmid syndrome is more common than previously thought

To estimate how common the condition is, Mount Sinai researchers collaborated with genetic testing laboratories, academic medical centers and autism research programs. The research team analyzed data from approximately 180,000 people with autism who had undergone genetic testing.

The analysis combined information from 10 separate sources, including GeneDx, Labcorp, Ambry Genetics, SPARK Research, the Autism Sequencing Consortium and several major children’s hospitals.

After accounting for undiagnosed cases, limitations of genetic testing and people with Phelan-McDiarmid syndrome who do not meet the criteria for autism, researchers estimated the prevalence at 13.7 per 100,000 people. This equals approximately 1 in 7,300 people.

The estimate represents a significant increase from previous figures and suggests that more than 45,000 people in the United States may have Phelan-McDiarmid syndrome.

“The wide disparity between known and probable cases is likely due in large part to the fact that many people with developmental disorders and autism have never had genetic testing,” said Tess Levy, M.A., a certified genetic counselor at the Seaver Autism Center, assistant professor of psychiatry at the Icahn School of Medicine at Mount Sinai and lead author of the paper.

Why genetic testing matters

Researchers say that broader access to genetic testing could help identify people who are currently undiagnosed.

“Knowledge is power, so we encourage all children with autism to undergo genetic testing. These genetic discoveries will allow researchers to design more targeted clinical trials for potential treatments. I truly believe that gene discovery will lead to successful new treatments,” said Joseph D. Buxbaum, Ph.D., director of the Seaver Autism Center, co-founder of the Autism Sequencing Consortium and lead author of the paper.

The study, supported by CureSHANK and Neuren Pharmaceuticals, is described as one of the most comprehensive attempts to date to estimate how many people may be affected by Phelan-McDiarmid syndrome.

“Neuren Pharmaceuticals, in collaboration with the Seaver Autism Center at Mount Sinai and CureSHANK, initiated this groundbreaking PMS prevalence study because identifying these individuals is an ethical imperative as new treatments approach reality. Without a diagnosis, patients cannot benefit from these advances,” said Dr. Rachel Gross, director of external innovation and patient advocacy at Neuren Pharmaceuticals.

New Phelan-McDiarmid syndrome treatments entering clinical trials

The findings come at a critical time for Phelan-McDiarmid syndrome research. Several clinical trials are currently underway, including precision medicine approaches targeting the underlying biology of the condition.

For people with Phelan-McDiarmid syndrome and their families, receiving a genetic diagnosis offers more than an explanation for symptoms. It may also provide access to specialized medical care, research studies, clinical trials, patient support networks and potentially disease-modifying treatments.

“This study confirms what many families, clinicians and advocates have long suspected,” said Geraldine Bliss, CureSHANK board chair. “There are likely tens of thousands of people with Phelan-McDiarmid syndrome who have never had a genetic diagnosis. With multiple treatments advancing into clinical trials, finding these patients is more important than ever.”

The results also strengthen CureSHANK’s efforts to expand access to genetic testing and support the goals of Start Genetic, a global awareness campaign that encourages patients, families, healthcare providers and advocacy groups to put genetics first.

The broader message is that advances in precision medicine can only reach patients who are first identified and diagnosed.