This “rare” autism-linked genetic disorder may be far more common than scientists thought

Phelan-McDermid syndrome is a rare genetic disorder caused by a deletion or mutation involving the SHANK3 gene on chromosome 22. It can lead to a broad range of medical, intellectual, and behavioral challenges. Most people with the syndrome also meet the criteria for autism spectrum disorder, and changes affecting SHANK3 are believed to account for as many as one percent of autism spectrum disorder cases.

Genetic Data Reveal a Much Larger Population

To estimate how common the condition may be, Mount Sinai researchers worked with genetic testing laboratories, academic medical centers, and autism research programs. The team examined data from nearly 180,000 people with autism who had undergone genetic testing.

Their analysis combined information from ten separate sources, including GeneDx, Labcorp, Ambry Genetics, the SPARK research study, the Autism Sequencing Consortium, and several major children's hospitals.

After accounting for undiagnosed cases, limits in genetic testing, and people with Phelan-McDermid syndrome who do not meet the criteria for autism, the researchers estimated a prevalence of 13.7 cases per 100,000 people. That works out to about 1 in 7,300 individuals.

The estimate represents a major change from previous figures and suggests that more than 45,000 people in the United States could be living with Phelan-McDermid syndrome.

"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.

Why Genetic Testing Could Matter

The researchers say broader access to genetic testing could help identify people who currently have no diagnosis.

"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.

Supported by CureSHANK and Neuren Pharmaceuticals, the study is described as one of the most comprehensive attempts yet to estimate how many people may have Phelan-McDermid syndrome.

"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. Patients cannot benefit from these advances if they never receive a diagnosis," said Rachel Groth, PhD, Head of External Innovation and Patient Advocacy at Neuren Pharmaceuticals.

New Treatments Are Moving Into Clinical Trials

The findings come at an important time for Phelan-McDermid syndrome research. Several clinical trials are now underway, including precision medicine approaches aimed at the biology underlying the disorder.

For people with the condition and their families, receiving a genetic diagnosis can now mean more than simply learning the cause of their 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 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 also reinforce CureSHANK's push to expand access to genetic testing and support the goals of Start Genetic, a global awareness campaign encouraging patients, families, health care providers, and advocacy groups to think genetic first.

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