Patients cannot benefit from precision medicine if they are never diagnosed
A condition once considered vanishingly rare has been quietly present in tens of thousands of lives, unrecognized and unnamed. New research from Mount Sinai has revised the prevalence of Phelan-McDermid syndrome to one in every 7,300 people — a figure that implies more than 45,000 Americans carry this genetic diagnosis without knowing it. The discovery arrives at a moment when clinical trials are opening doors that only a diagnosis can unlock, making the distance between a person and their genetic truth not merely a medical gap, but a human one.
- A syndrome long considered rare has been dramatically underestimated, with new data suggesting the true prevalence is far higher than the medical community assumed.
- Tens of thousands of people are living without answers — navigating disability, behavioral challenges, and medical complexity without the clarity a diagnosis would provide.
- Insurance barriers, incomplete genetic tests, and a systemic failure to offer screening to children with developmental disabilities are keeping families in the dark.
- Multiple clinical trials are now underway, meaning an undiagnosed person is not just missing a label — they are missing access to precision therapies that could alter the course of their condition.
- Researchers, genetic counselors, and patient advocates are calling for a cultural shift in medicine: think genetic first, test more broadly, and treat diagnosis itself as an act of care.
A study led by the Seaver Autism Center at Mount Sinai has upended longstanding assumptions about Phelan-McDermid syndrome, estimating its prevalence at 13.7 per 100,000 people — roughly one in 7,300 — a figure that implies more than 45,000 Americans are living with the condition undiagnosed. The syndrome, caused by a deletion or mutation in the SHANK3 gene on chromosome 22, produces intellectual disability, behavioral difficulties, and medical complications, and the majority of those affected also meet criteria for autism spectrum disorder.
To reach this estimate, researchers analyzed genetic testing data from nearly 180,000 individuals with autism, drawing from ten independent sources including commercial laboratories, major children's hospitals, and large research consortia. After accounting for undiagnosed cases, testing limitations, and individuals who don't meet autism criteria, they arrived at a prevalence dramatically higher than prior estimates had suggested.
The reasons so many cases go undetected are structural. Many children with developmental disabilities are never offered genetic testing. Insurance barriers block access. And even when testing occurs, current methods often fail to adequately evaluate the SHANK3 gene. Each undiagnosed person is, in the words of one advocate, a family still searching — cut off from specialized care, support communities, and research participation.
The urgency is sharpened by timing. Clinical trials for Phelan-McDermid syndrome are now advancing, with precision medicine approaches targeting the disorder's underlying biology. For the first time, a diagnosis is not just an explanation — it is a doorway to emerging therapies that may genuinely modify the disease's course. Researchers express confidence that effective treatments will emerge within five years, but those treatments can only reach people who know they need them. Expanding genetic testing access, advocates and scientists agree, has become a moral imperative.
A genetic condition that researchers once thought was exceedingly rare may actually affect one in every 7,300 people—a staggering revision that suggests more than 45,000 Americans are living with Phelan-McDermid syndrome without knowing it. The discovery emerged from a study led by the Seaver Autism Center for Research and Treatment at Mount Sinai, published in June in the journal Autism Research, and it has forced the medical field to reckon with a diagnosis gap of historic proportions.
Phelan-McDermid syndrome is caused by a deletion or mutation in the SHANK3 gene on chromosome 22. The condition produces a constellation of challenges—medical complications, intellectual disability, behavioral difficulties—and the vast majority of people who carry it also meet the diagnostic criteria for autism spectrum disorder. Researchers have long suspected that SHANK3 mutations account for roughly one percent of all autism cases, but the true prevalence of the syndrome itself remained murky, hidden behind incomplete testing and limited access to genetic screening.
To arrive at their new estimate, Mount Sinai scientists undertook one of the most comprehensive prevalence studies ever attempted. They analyzed genetic testing data from nearly 180,000 individuals diagnosed with autism, pooling information from ten independent sources: commercial laboratories like GeneDx, Labcorp, and Ambry Genetics; the SPARK research study; the Autism Sequencing Consortium; and several major children's hospitals. After adjusting for cases that went undiagnosed, for the limitations of existing tests, and for individuals with Phelan-McDermid syndrome who do not meet autism criteria, they calculated a prevalence of 13.7 cases per 100,000 people.
The gap between known cases and estimated cases is not mysterious. Tess Levy, a certified genetic counselor and assistant professor of psychiatry at Mount Sinai's Icahn School of Medicine, pointed to a simple but consequential reality: many children with developmental disabilities and autism are never offered genetic testing in the first place. Families encounter insurance barriers. Tests that are performed often fail to adequately evaluate the SHANK3 gene. The result is a population of undiagnosed individuals, each one a person without answers, without connection to specialized care, without access to the support communities and research opportunities that a diagnosis unlocks.
The timing of this discovery is not incidental. Multiple clinical trials for Phelan-McDermid syndrome are now underway, including precision medicine approaches designed to target the underlying biology of the disorder. For the first time, a genetic diagnosis of this condition is not merely an explanation—it is a pathway to specialized treatment, to research participation, to emerging therapies that may actually modify the course of the disease. Joseph D. Buxbaum, director of the Seaver Autism Center, expressed confidence that within five years, successful new treatments will emerge from these genetic insights. But those treatments can only help people who know they have the condition.
Geraldine Bliss, board chair of CureSHANK, an advocacy organization dedicated to the syndrome, framed the stakes plainly. Every undiagnosed individual represents not a missing statistic but a family still searching for answers, a person isolated from support, a patient who may never learn of clinical trials or emerging therapies. As treatments move from laboratory to clinic, identifying these individuals has become what she called a moral imperative. The findings support broader efforts to expand genetic testing access and to encourage patients, families, and health care providers to think genetic first—to recognize that precision medicine cannot help anyone who remains undiagnosed.
Notable Quotes
Knowledge is power. These genetic findings allow researchers to design more targeted clinical trials for potential therapies, and within the next five years, we'll see successful examples of new treatments coming from these genetic discoveries.— Joseph D. Buxbaum, Director of the Seaver Autism Center
Every undiagnosed individual 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.— Geraldine Bliss, CureSHANK Board Chair
The Hearth Conversation Another angle on the story
Why did it take so long to realize how common this condition actually is?
Because genetic testing wasn't routine. Most children with autism or developmental disabilities never got tested for specific genetic causes. The tests that existed often didn't look carefully enough at the SHANK3 gene. You can't count what you're not looking for.
So this is really about access to testing, not about the condition itself changing?
Exactly. The condition didn't become more common overnight. What changed is that researchers finally pooled enough testing data from enough places to see the real picture. They looked at 180,000 cases and adjusted for all the people who should have been tested but weren't.
What does a diagnosis actually change for someone with Phelan-McDermid syndrome right now?
Everything, potentially. Before, you had a child with autism and developmental delays, but no explanation. Now you have a genetic diagnosis—and that opens doors. You can connect with other families who have it. You can enroll in clinical trials. You can access specialized care. And soon, you might have access to actual treatments.
The article mentions precision medicine approaches. What does that mean in practical terms?
It means therapies designed specifically to address what's broken at the genetic level. Not just managing symptoms, but potentially fixing the underlying problem. That's the promise that's driving the clinical trials forward right now.
How many people are we talking about who don't know they have this?
More than 45,000 in the United States alone. Most of them are probably diagnosed with autism or intellectual disability, but they've never had the genetic test that would tell them why.