HOUSTON — For years, the parents of 10-year-old Owen Johnson held onto a persistent intuition that autism alone could not fully account for the complex mosaic of symptoms their son had experienced since his earliest toddler years.
Owen was originally diagnosed with autism at the age of three after missing expected speech milestones and struggling to form meaningful connections with his peers at a Houston preschool. His pediatrician initially recommended early intervention therapies that brought some modest improvements before gradually losing their effectiveness. As the years passed, his parents watched a widening developmental gap emerge between Owen and his twin sister, Alice, as well as his older sisters, Audrey and Evelyn.
“He had always been a very happy child in his early toddler years, and then he would just get so withdrawn,” his mother, Jennifer Johnson, recalled. “I was really concerned.”
Determined to seek deeper answers, the family turned to medical diagnostics. In 2021, Owen’s doctor collected a blood sample and submitted it for comprehensive genetic testing. Yet, the initial results yielded no novel insights or actionable data to explain the specific trajectory of Owen’s symptoms.
“It’s a helpless feeling,” said his father, Dr. Peter Johnson, a neurologist. “If you don’t have an answer, then what can you do?”
Unbeknownst to the family at the time, across the city of Houston, a parallel scientific discovery was quietly unfolding. Dr. Ryan Dhindsa and his research team at the Jan and Dan Duncan Neurological Research Institute (NRI), housed at Texas Children’s Hospital, were investigating a suspicious gene mutation identified during broader laboratory research into Parkinson’s disease. Before long, Dhindsa’s lab realized that this exact genetic anomaly was directly tied to neurodevelopmental conditions such as autism—and that it finally offered a coherent explanation for Owen’s mysterious symptoms.
Searching for an explanation
In his earliest days, Owen’s development appeared remarkably typical to his parents. He began speaking later than his peers and developed intense, singular fixations—such as becoming profoundly preoccupied with the color red—but these behaviors were easily dismissed as ordinary eccentricities of toddlerhood. Even Owen’s teachers expressed genuine surprise when the Johnsons formally informed his preschool of his autism diagnosis.
However, over the subsequent years, the family watched a heartbreaking transformation take place. Owen shifted from a bright, energetic boy into a child who was frequently moody, unhappy, and distressed. He had always adored playing and singing alongside his three sisters, including his older twin sisters, Audrey and Evelyn, and his twin sister, Alice. Gradually, he began struggling to maintain focus at school and stopped participating in the annual Mother’s Day musical performance that he and his siblings had traditionally shared.
The Johnsons found themselves trapped in a frustrating medical limbo, unable to shake the conviction that the clinical picture was incomplete. Without any alternative medical diagnosis beyond a broad autism spectrum label, their only recourse was to rely on Owen’s pediatrician and developmental therapists to periodically adjust his behavioral therapies and medications.
“You just want so badly to do something for them and do everything you can to make it better for them,” Jennifer Johnson said. “It was very frustrating.”
A suspicious gene mutation
While the Johnsons navigated these daily challenges, Dr. Dhindsa and his colleagues at the Duncan NRI were deeply immersed in mapping genetic risk factors underlying Parkinson’s disease.
Human genetics dictates that every child is born with roughly 70 spontaneous genetic mutations that were not directly inherited from their biological parents. While the vast majority of these spontaneous alterations are entirely harmless, an extremely small fraction can disrupt critical biological pathways and lead to severe genetic disorders, explained Dhindsa, who serves as a principal investigator at the Duncan NRI and an assistant professor at the Baylor College of Medicine.
“Sometimes we get unlucky, and that mutation hits a really important gene,” he noted.
Pinpointing disease-linked genes within the human genome is a monumental task, given that human DNA comprises more than 3 billion base pairs. To tackle this computational challenge, Dhindsa’s laboratory leveraged artificial intelligence and advanced sequencing tools to analyze genetic data drawn from approximately 800,000 patients, comparing individuals diagnosed with Parkinson’s disease against healthy controls.
The massive datasets revealed a striking pattern: a significant concentration of Parkinson’s patients carried a mutation in a specific gene known as ITSN1, which is responsible for producing a protein vital for facilitating communication between brain cells. Over subsequent years of rigorous testing, Dhindsa’s team established that individuals carrying an ITSN1 genetic variant face a risk of developing Parkinson’s disease that is roughly 10 times higher than that of the general population.
Crucially, as the researchers dove deeper into the function of the gene, they noticed something unexpected. ITSN1 variants also appeared at a notably higher frequency in an entirely different patient demographic: children who had been diagnosed with autism and other complex neurodevelopmental disorders.
An obscure answer
By mid-2022, the long search for answers took an abrupt turn when Jennifer Johnson opened an email notification from the commercial laboratory that had conducted Owen’s genetic panel a year earlier.
The correspondence explained that the facility had recently become aware of emerging academic research identifying ITSN1 variants as “likely pathogenic.” This classification indicated that strong, accumulating evidence suggested the variant could directly cause neurodevelopmental disorders mirroring autism. However, the letter provided little additional clinical context or guidance.
The Johnsons immediately turned to the internet, scouring medical literature, but found virtually nothing to clarify what the finding meant for Owen’s long-term prognosis or daily life. When they consulted his existing network of doctors and therapists, they discovered that none of them had ever encountered the term ITSN1 either.
“There was a little piece of the puzzle that was maybe filled in, but it just didn’t give a clear enough picture,” Jennifer Johnson reflected.
Seeking specialized expertise, the family brought Owen to Texas Children’s Hospital the following year to consult pediatric neurologist Dr. Sarah Risen. Dr. Risen ordered follow-up genetic evaluations that formally confirmed the presence of the ITSN1 variant. Furthermore, she adjusted Owen’s medication regimen to incorporate pharmaceuticals designed to better target symptoms associated with the specific genetic finding.
In early 2025, Dr. Risen delivered another pivotal piece of news: a scientist at the Duncan NRI was actively studying the very same genetic variant as part of his neurological research. She subsequently facilitated a direct connection between the Johnson family and Dr. Dhindsa.
A puzzling diagnosis
Today, Dr. Dhindsa’s laboratory remains among a select few scientific teams worldwide actively investigating ITSN1, largely because the genetic variant is exceptionally rare. Current estimates suggest that roughly one in every 5,000 people is born with an ITSN1 variant, according to Dhindsa.
Despite ongoing research, the variant continues to baffle neuroscientists because its clinical penetrance and expressivity are highly unpredictable. In approximately 60% of cases where a child inherits the variant from a parent, that parent appears entirely unaffected by any clinical symptoms, Dhindsa explained.
Clinically, children who present with ITSN1-related syndrome are almost universally given initial diagnoses of autism and attention-deficit/hyperactivity disorder (ADHD). Yet, curiously, most adult patients who carry ITSN1 variants and go on to develop Parkinson’s disease later in life report no personal history of neurodevelopmental disorders during their childhood years.
Such profound biological mysteries are standard territory for researchers at the Duncan NRI, an institution dedicated to unraveling the genetic underpinnings of rare pediatric brain disorders.
Understanding the precise genomic entry points is fundamental to mapping how the human brain fails to function properly or why it becomes uniquely vulnerable to neurodegeneration later in life, said Dr. Huda Zoghbi, an acclaimed neurogeneticist and the founding director of the Duncan NRI. Gaining this foundational knowledge allows scientists to envision pathways for neutralizing harmful genetic variants or designing targeted medications and therapies.
“Once you know that,” Dr. Zoghbi said, “we can then begin to say, ‘How do you reverse it?’”
Complex genetic research
The Johnsons first met Dr. Dhindsa last year, shortly after he served as a co-corresponding author on a landmark study establishing the statistical link between ITSN1 variants and elevated Parkinson’s risk. They are presently among a cohort of roughly 20 families collaborating closely with Dhindsa’s laboratory to shed light on the realities of ITSN1-related syndrome.
A central component of this collaboration involves a natural history study, wherein Dhindsa’s team tracks individuals with ITSN1 variants over extended periods to document the natural progression of symptoms. While some individuals experience relatively mild manifestations—such as manageable ADHD or moderate learning disabilities—others face more severe neurological challenges, including epileptic seizures or dramatic language regression that can result in the gradual loss of speech as late as their teenage years, Dhindsa noted.
Simultaneously, the Duncan NRI is deploying sophisticated genomic techniques to investigate the cellular mechanisms of ITSN1 variants.
In a painstaking process that took approximately 18 months, Dhindsa’s lab extracted a skin cell sample from Owen and utilized advanced gene-editing technology to reprogram the cells into induced pluripotent stem cells. From there, the researchers successfully differentiated those stem cells into specialized brain cells—some carrying the patient’s specific ITSN1 variant and others serving as healthy controls.
In tandem, researchers are utilizing animal models, observing mice across their lifespans to evaluate how the genetic variant alters learning capacity, memory formation, and broader cognitive performance.
“There’s very little understanding of how this gene actually can lead to either autism or Parkinson’s, and critically, why some people can be walking around with the variant and healthy while others can’t,” Dhindsa said. “We’re trying to understand all the different components of this puzzle.”
Bringing families on the journey
While the ultimate objective of the Duncan NRI’s bench research is the development of transformative therapies and medications for rare disease patients, Dr. Zoghbi emphasizes that scientific translation is inherently time-consuming.
Many families experience an initial wave of relief upon discovering a definitive genetic root cause for their child’s lifelong developmental hurdles. However, that early optimism can gradually give way to the exhausting realities of the lengthy research pipeline, making it vital for investigators to maintain a collaborative partnership with affected families, Zoghbi explained.
“We give them hope, but we also take them along with us on the journey,” she said. “They know we’re doing all the steps, one by one, and as fast as we can.”
For the Johnsons, confronting the unknowns surrounding ITSN1-related syndrome remains a sobering experience. Hearing clinical accounts of older children who have experienced profound speech regression presents a constant emotional weight.
Furthermore, because clinical guidelines for such a rare variant are virtually nonexistent, the family often finds themselves bridging the gap by sharing the latest academic discoveries directly with Owen’s educational and therapeutic teams.
Even so, the family maintains a spirit of cautious optimism. Owen and his twin sister recently celebrated their tenth birthday. Owen remains an active child who loves playing tag with his siblings and has recently developed a keen fascination with dinosaurs.
A newly adjusted medication regimen has yielded noticeable improvements in his daily mood and cognitive concentration. Following a family relocation to Tomball, Owen’s new school has seamlessly accommodated his educational needs by embedding his specialized therapists directly into his classroom environment throughout the school day.
“They help me with work at school,” Owen said. “They help me pay attention.”
The family draws significant encouragement from the ongoing breakthroughs at the Duncan NRI. While Owen will likely require dedicated support systems throughout his life, his parents cling to the hope that continued scientific discovery will soon yield targeted therapies capable of halting further regression.
“Of course, we would like for him to be an independent, functioning adult one day,” Jennifer Johnson said. “We’re hoping [Dr. Dhindsa’s] work can yield that.”
