New research conducted by a team of scientists at the Seaver Autism Center for Research and Treatment at Mount Sinai has revealed that Phelan-McDermid syndrome (PMS)—a complex genetic condition often associated with autism spectrum disorder—is likely far more common than previous clinical estimates had suggested. The findings, which were recently published in the journal Autism Research, provide a revised prevalence rate of approximately 1 in 7,300 individuals, a figure that carries significant implications for clinical practice, genetic screening policies, and the development of future therapeutic interventions.
The Genetic Foundations of PMS
Phelan-McDermid syndrome is a rare genetic disorder characterized by a deletion or mutation involving the SHANK3 gene, located on chromosome 22. This specific genetic disruption is known to have a profound impact on neurological development, often resulting in a wide spectrum of medical, intellectual, and behavioral challenges. Because the SHANK3 gene plays a critical role in the formation and function of synapses—the connections between neurons in the brain—its dysfunction is frequently linked to broader developmental issues.
Notably, a large proportion of individuals diagnosed with PMS also meet the clinical criteria for autism spectrum disorder (ASD). Current medical literature suggests that alterations affecting the SHANK3 gene may account for as many as one percent of all diagnosed cases of autism spectrum disorder. Given the complexity of the syndrome, clinicians often struggle to identify the condition in patients who present with non-specific developmental delays, meaning that many individuals may be living with the syndrome without a formal genetic confirmation of their underlying diagnosis.
Genetic Data Reveal a Much Larger Population
To arrive at a more accurate estimate of the syndrome’s prevalence, the research team at Mount Sinai spearheaded an expansive, multi-institutional study. Recognizing the limitations of relying on small, localized cohorts, the researchers collaborated with a diverse array of genetic testing laboratories, prominent academic medical centers, and established autism research programs. By aggregating data from nearly 180,000 individuals who had undergone genetic testing due to concerns regarding autism or developmental delays, the team sought to create a representative statistical model.
The analysis was a massive undertaking, integrating information from ten separate, high-fidelity sources. Key contributors to the data pool included organizations such as GeneDx, Labcorp, Ambry Genetics, the SPARK research study, and the Autism Sequencing Consortium, alongside several major children’s hospitals that specialize in neurodevelopmental conditions.
After processing this data, the researchers performed a rigorous adjustment to account for several confounding factors. These included the number of individuals currently living with the condition who remain undiagnosed, the technical limitations inherent in some routine genetic testing panels, and, crucially, those individuals with PMS who do not exhibit the typical symptoms associated with autism spectrum disorder. By synthesizing these variables, the team calculated a prevalence rate of 13.7 cases per 100,000 people. When translated into a more relatable statistic, this suggests that roughly 1 in 7,300 people in the general population may be affected by the condition.
This new estimate represents a substantial departure from previous, more conservative figures. If these findings hold true on a national scale, it indicates that more than 45,000 people in the United States alone could be living with Phelan-McDermid syndrome—a significant increase from earlier projections that often underestimated the condition’s reach.
Tess Levy, MSc, an Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai and a certified genetic counselor at the Seaver Autism Center, served as the first author of the paper. She suggests that the historical discrepancy between known cases and the new, higher estimate is largely a byproduct of systemic gaps in the healthcare landscape.
"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," Levy explained. "Families may also face insurance barriers, or they may receive tests that are not comprehensive enough to adequately evaluate the SHANK3 gene. When the right testing isn’t performed, the diagnosis remains hidden."
Why Genetic Testing Could Matter
The implications of this study extend far beyond statistical record-keeping. The researchers emphasize that broader, more consistent access to genetic testing is not merely a diagnostic preference but a fundamental clinical necessity. By identifying individuals who currently have no formal diagnosis, the medical community can provide families with clarity, access to support networks, and, perhaps most importantly, potential pathways to specialized care.
Joseph D. Buxbaum, PhD, the Director of the Seaver Autism Center, a co-founder of the Autism Sequencing Consortium, and the senior author of the paper, believes the time for a shift in diagnostic strategy is now. "We recommend that every child with autism undergo genetic testing, because knowledge is power," Buxbaum stated. "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."
The study, which received support from both CureSHANK and Neuren Pharmaceuticals, is being recognized as one of the most comprehensive efforts to date to quantify the prevalence of PMS. The involvement of pharmaceutical and advocacy partners underscores the urgency of the mission. For those in the biotechnology sector, identifying the patient population is the first step toward bringing life-changing therapies to market.
Rachel Groth, PhD, the Head of External Innovation and Patient Advocacy at Neuren Pharmaceuticals, highlighted the ethical imperative driving this research. "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," Groth said. "Patients cannot benefit from these advances if they never receive a diagnosis."
New Treatments Are Moving Into Clinical Trials
The timing of these findings is critical, as the research landscape for Phelan-McDermid syndrome is currently entering a period of unprecedented activity. Several clinical trials are already underway, utilizing precision medicine approaches that target the specific biological pathways underlying the disorder. For families who have spent years navigating the challenges of a child’s developmental delays without knowing the exact genetic cause, a diagnosis can act as a bridge to a new era of medical management.
Receiving a genetic diagnosis provides more than just an explanation for symptoms; it opens doors to specialized medical care, engagement with clinical research, and access to emerging, disease-modifying treatments that were previously unavailable.
Geraldine Bliss, the Board Chair of CureSHANK, expressed the relief and validation felt by the advocacy community upon the release of these findings. "This study confirms what many families, clinicians, and advocates have suspected for years," Bliss noted. "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 advocacy efforts of organizations like CureSHANK, which are pushing to expand access to genetic testing through initiatives like the "Start Genetic" campaign. This global awareness movement encourages patients, families, and healthcare providers to prioritize genetic inquiry as a primary step in the evaluation of developmental conditions.
Ultimately, the research led by the Seaver Autism Center serves as a reminder that the promise of precision medicine is inherently limited by the ability to identify those who need it most. As the medical community continues to refine its understanding of the genetic architecture of autism and developmental disabilities, the path forward appears increasingly dependent on the accessibility of genetic data. By closing the diagnostic gap, researchers hope to ensure that the next generation of scientific breakthroughs can effectively reach the thousands of individuals who remain in the shadows of an undiagnosed condition.
