Phelan-McDermid syndrome may be more common than previously believed

New research, led by scientists from the Seaver Autism Center for Research and Treatment at Mount Sinai and published June 28 in Autism Research, has estimated that Phelan-McDermid syndrome (PMS) affects approximately 1 in 7,300 people, making it dramatically more common than previous estimates suggested.

Phelan-McDermid syndrome is a rare genetic condition caused by deletion or mutation of the SHANK3 gene on chromosome 22. The syndrome can cause a wide range of medical, intellectual, and behavioral challenges. The majority of patients with the syndrome also meet the criteria for autism spectrum disorder, and SHANK3 deletions or mutations are thought to account for up to one percent of autism spectrum disorder cases.

In collaboration with genetic testing laboratories, academic medical centers, and autism research programs, Mount Sinai researchers analyzed data from nearly 180,000 individuals with autism who underwent genetic testing. They combined data from ten independent sources, including GeneDx, Labcorp, Ambry Genetics, the SPARK research study, the Autism Sequencing Consortium, and several leading children's hospitals.

After adjusting for undiagnosed cases, testing limitations, and individuals with Phelan-McDermid syndrome who do not meet criteria for autism, investigators estimated a prevalence of 13.7 cases per 100,000 people, equivalent to about 1 in 7,300 individuals. The new findings represent a dramatic shift from previous estimates and indicate that more than 45,000 people in the United States may be living with the condition.

"The large gap between known and estimated cases is likely due in large part to the fact that many individuals with developmental disabilities and autism are never offered genetic testing. Families may also face insurance barriers or may receive tests that do not adequately evaluate the SHANK3 gene," said Tess Levy, MSc, Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai, a certified genetic counselor at the Seaver Autism Center, and first author of the paper.

"We recommend that every child with autism undergo genetic testing, because knowledge is power. These genetic findings allow researchers to design more targeted clinical trials for potential therapies. I truly believe that within the next five years, we'll see successful examples of new treatments coming from these genetic discoveries," said Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center, co-founder of the Autism Sequencing Consortium, and senior author of the paper.

The study, supported by CureSHANK and Neuren Pharmaceuticals, represents one of the most comprehensive efforts ever undertaken to estimate the prevalence of Phelan-McDermid syndrome.

The publication arrives at a pivotal moment for the field. Multiple Phelan-McDermid syndrome clinical trials are underway, including precision medicine approaches designed to address the underlying biology of the disorder. For individuals and families affected by this condition, a genetic diagnosis is no longer simply an explanation. It is increasingly a gateway to specialized care, research opportunities, clinical trials, patient support communities, and potentially disease-modifying therapies.

"This study confirms what many families, clinicians, and advocates have suspected for years," said CureSHANK Board Chair, Geraldine Bliss. "There are likely tens of thousands of individuals with Phelan-McDermid syndrome who have never received a genetic diagnosis. At a time when multiple therapeutics are advancing into clinical trials, finding these individuals has never been more important."

The findings support the urgency behind CureSHANK's efforts to expand access to genetic testing and the broader goals of Start Genetic, a global awareness campaign launched to encourage patients, families, health care providers, and advocacy organizations to think genetic first. They also underscore a fundamental truth: patients cannot benefit from precision medicine if they are never diagnosed.

"Every undiagnosed individual represents more than a missing statistic," Ms. Bliss said. "It represents a family searching for answers, a person disconnected from support, and a patient who may miss opportunities to participate in research or access emerging therapies. As treatments move closer to reality, identifying these individuals becomes a moral imperative."