New research led by a multi-institutional team of scientists at the Seaver Autism Center for Research and Treatment at Mount Sinai suggests that Phelan-McDermid syndrome (PMS) may be much more common than earlier estimates indicated. The findings, which were recently published in the journal Autism Research, provide a new statistical framework for understanding the reach of this rare genetic condition, estimating that the disorder affects approximately 1 in 7,300 people. This revised figure represents a significant increase in the known prevalence of the syndrome and suggests that thousands of individuals may be living without a proper diagnosis.
Phelan-McDermid syndrome is a rare genetic disorder typically caused by a deletion or mutation involving the SHANK3 gene located on chromosome 22. This specific gene is critical for the development and function of synapses—the connections between brain cells that allow for communication within the nervous system. Because the SHANK3 gene plays such a fundamental role in neurological architecture, its absence or impairment can lead to a broad range of medical, intellectual, and behavioral challenges. These often include global developmental delays, absent or severely delayed speech, impaired motor skills, and various medical comorbidities such as seizures or gastrointestinal issues.
The connection between Phelan-McDermid syndrome and autism spectrum disorder (ASD) is particularly strong. Most individuals diagnosed with the syndrome also meet the clinical criteria for autism. In fact, genetic changes affecting the SHANK3 gene are believed to account for as many as one percent of all autism spectrum disorder cases globally. Despite this clear link, the syndrome has historically been classified as an ultra-rare condition, a designation that the new Mount Sinai study seeks to re-evaluate through a comprehensive analysis of modern genetic data.
Genetic Data Reveal a Much Larger Population
To estimate how common the condition may truly be, the Mount Sinai researchers spearheaded a massive collaborative effort, working alongside genetic testing laboratories, academic medical centers, and large-scale autism research programs. The scale of the study was unprecedented for this specific disorder; the team examined and analyzed genetic data from nearly 180,000 people with autism who had undergone various forms of genetic testing.
By casting such a wide net, the researchers were able to move beyond small, localized clinical samples and look at the broader landscape of neurodevelopmental genetics. Their analysis combined information from ten separate and highly reputable sources, creating a robust dataset that included contributions from GeneDx, Labcorp, and Ambry Genetics. Additionally, the study integrated data from the SPARK research study—the largest long-term study of autism in the United States—as well as the Autism Sequencing Consortium and several major children’s hospitals across the country.
The methodology required a careful balancing act. The researchers had to account for several variables that often skew prevalence data, including undiagnosed cases in the general population, the historical limits of genetic testing technologies, and the subset of people with Phelan-McDermid syndrome who do not meet the formal diagnostic criteria for autism. After applying these statistical corrections to their massive dataset, the researchers estimated a prevalence rate of 13.7 cases per 100,000 people. When translated into more common terms, that works out to approximately 1 in 7,300 individuals.
This new estimate represents a major shift from previous figures, which often characterized the syndrome as affecting only a few thousand people worldwide. Under this new model, the researchers suggest that more than 45,000 people in the United States alone could be living with Phelan-McDermid syndrome. The discrepancy between the number of currently diagnosed patients and this new estimate highlights a significant gap in the healthcare system’s ability to identify and support these individuals.
"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," said Tess Levy, MSc, Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai and a certified genetic counselor at the Seaver Autism Center. Levy, who served as the first author of the paper, noted that the barriers to diagnosis are often systemic rather than medical. "Families may also face insurance barriers or may receive tests that do not adequately evaluate the SHANK3 gene. Without specific, high-resolution testing, the underlying cause of a child’s developmental challenges can remain a mystery indefinitely."
Why Genetic Testing Could Matter
The researchers emphasize that the implications of this study extend far beyond statistical curiosity. They argue that broader, more equitable access to genetic testing is a clinical necessity that could help identify thousands of people who currently have no specific diagnosis for their symptoms. For many families, receiving a diagnosis of Phelan-McDermid syndrome is the end of a long and exhausting "diagnostic odyssey" characterized by years of uncertainty and ineffective treatments.
The Seaver Autism Center team advocates for a proactive approach to neurodevelopmental care. They suggest that genetic testing should not be viewed as a luxury or a secondary option, but as a primary diagnostic tool for any individual presenting with symptoms on the autism spectrum or with significant developmental delays.
"We recommend that every child with autism undergo genetic testing, because knowledge is power," said Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center, co-founder of the Autism Sequencing Consortium, and senior author of the paper. Dr. Buxbaum’s perspective is rooted in the emerging field of precision medicine, which seeks to tailor medical treatments to the specific genetic profile of the patient.
"These genetic findings allow researchers to design more targeted clinical trials for potential therapies," Dr. Buxbaum explained. "I truly believe that within the next five years, we’ll see successful examples of new treatments coming from these genetic discoveries. But those treatments can only be effective if we know which patients have the specific genetic markers that the drugs are designed to target."
The study, which received vital support from the advocacy organization CureSHANK and Neuren Pharmaceuticals, is being described as one of the most comprehensive and rigorous attempts yet to quantify the population of people living with Phelan-McDermid syndrome. The partnership between academic researchers, pharmaceutical innovators, and patient advocates underscores the shared urgency in finding and helping this "hidden" population.
"Neuren Pharmaceuticals initiated this landmark PMS prevalence study in collaboration with the Seaver Autism Center at Mount Sinai and CureSHANK because, with new treatments moving closer to reality, identifying these individuals has become an ethical imperative," said Rachel Groth, PhD, Head of External Innovation and Patient Advocacy at Neuren Pharmaceuticals. Dr. Groth pointed out that the development of new drugs is only half the battle. "Patients cannot benefit from these advances if they never receive a diagnosis. We have a responsibility to ensure that the science of treatment is matched by the science of identification."
New Treatments Are Moving Into Clinical Trials
The publication of these findings comes at a pivotal moment for the Phelan-McDermid syndrome community. The research landscape has shifted from basic discovery to active clinical intervention. Several clinical trials are now underway, including precision medicine approaches that aim to address the specific biological pathways disrupted by SHANK3 mutations. These trials represent a new era of hope for families, moving away from generalized symptom management toward therapies that could potentially modify the course of the disorder.
For individuals with the condition and their families, receiving a genetic diagnosis is becoming increasingly transformative. In the past, a diagnosis might have provided a name for a condition but offered few practical changes in care. Today, however, a diagnosis of Phelan-McDermid syndrome can open doors to specialized medical protocols, enrollment in cutting-edge research studies, and participation in clinical trials for emerging medications. It also connects families to robust patient support networks where they can share experiences and resources with others facing similar challenges.
"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 results of the study also reinforce the mission of CureSHANK to expand global access to genetic testing. The organization is a vocal supporter of the "Start Genetic" campaign, an international awareness initiative that encourages patients, families, healthcare providers, and advocacy groups to prioritize genetic investigation early in the diagnostic process. The campaign’s core message—to "think genetic first"—is designed to bypass the traditional delays in diagnosis that have left so many individuals without the specialized care they require.
Ultimately, the study serves as a reminder that the success of precision medicine is entirely dependent on the accuracy of patient identification. As researchers at Mount Sinai and their partners continue to unravel the complexities of the SHANK3 gene, the focus remains on ensuring that the 45,000 Americans estimated to have the condition are given the opportunity to benefit from the next generation of medical breakthroughs. The broader message from the Seaver Autism Center is clear: while Phelan-McDermid syndrome may be rare, it is far more prevalent than the world realized, and every undiagnosed individual represents a missed opportunity for life-changing intervention.
