Researchers at Rady Children’s Institute for Genomic Medicine (RCIGM) in San Diego have successfully applied long-read genome sequencing to reveal the genetic underpinnings of complex psychiatric conditions in a 17-year-old patient, showcasing the potential of this advanced technology for clinical diagnosis and future gene therapies.
In the recent study, “Long-Read Genome Sequencing in Clinical Psychiatry: RFX3 Haploinsufficiency in a Hospitalized Adolescent With Autism, Intellectual Disability, and Behavioral Decompensation,” published in the American Journal of Psychiatry, researchers utilized the PacBio Revio platform, a long-read sequencing technology, to pinpoint the diagnosis of RFX3 haploinsufficiency syndrome in an adolescent with autism spectrum disorder and intellectual disability.
While testing children for genetic disorders, a percentage of young patients are found to have variants of uncertain significance that short-read sequencing is unable to decipher. That’s where long-read sequencing can shed some light. RCIGM clinicians have used this technology to understand and diagnose pediatric patients. Stephen Kingsmore, PhD, the RCIGM president and CEO, is well known in the genomics field for leading long-read studies on rare disease diagnostics.
Aaron D. Besterman, MD, a child psychiatrist and genetics researcher at RCIGM who co-authored the new study, told GEN that this was part of a larger project that primarily used short-read sequencing to study children with neurodevelopmental disorders. “The goal of this study was really to better characterize and understand who these kids are exactly,” Besterman said. Reaching a confirmed diagnosis can be a big step to improving the outcomes for these young patients.
A tale of two platforms
Investigators must face several considerations when choosing between long-read platforms for clinical diagnostics, particularly when cataloging complex structural variants.
Jonathan Sebat, PhD, director of the Verge Center at the University of California, San Diego, and a co-author of the study, told GEN that the team selected PacBio over the other major long-read sequencing platform, produced by the U.K.’s Oxford Nanopore (ONT). After weighing the pros and cons of both platforms, the team decided to use PacBio to maximize accuracy, Sebat said.
“Both technologies are progressing rapidly. They are quite complementary and are often used in combination,” Sebat said. “Historically, PacBio has had an advantage in terms of the accuracy of the sequencing reads. ONT has the ability to generate much longer reads, which is very useful for assembling the reads into a complete genome.”
“ONT has also made improvements to its sequencing accuracy so both platforms are strong contenders for eventually becoming a first-line comprehensive genetic test.”
Through PacBio sequencing, the San Diego team uncovered a complex arrangement with both deletions and duplications in the RFX3 gene, ultimately leading to a loss of function. This allowed them to categorize the variant and make a more certain and accurate diagnosis in the teenage patient.
The long view: Sequencing toward the future
The successful diagnosis provided significant relief for the patient’s family, delivering answers after years of uncertainty. Beyond personal closure, genetic insights from long-read sequencing also open avenues for community support, reproductive counseling, gene therapy, and tailored medical management strategies.
“The last important piece of this is medical management,” Besterman added. Through long-read sequencing, Besterman believes that a few cases in the study have the potential to uncover genes associated with autism and other medical conditions, which could prevent other patients from a diagnostic odyssey.
Despite its promising outcomes, the broader clinical adoption of long-read sequencing faces several barriers. The relatively high cost, limited accessibility, and the need for extensive medical genetics training among clinicians are currently holding back widespread use.
“I think it’s important that the general psychiatry field start to become more familiar with this technology because it will become more and more common and can play a very important role in making diagnoses that are not possible through any other means,” stated Besterman.
Looking ahead, the researchers emphasize the importance of integrating long-read sequencing into broader diagnostic pipelines, not as a replacement for short-read methods but as a powerful complement for cases where other tools fall short.
“Long-read sequencing is certainly the type of diagnostic technology that’s going to play a huge role in precision medicine moving forward. I think there will also be a lot of integration with other omics platforms and technology,” said Besterman. Instead of solely focusing on genetics, the integration of transcriptomics and proteomics, among others, with clinical data to inform diagnoses, should be considered.
As clinical implementation grows, the case from RCIGM underscores the importance of continued investment and innovation in genomic technologies, highlighting a hopeful path forward for complex psychiatric conditions previously considered diagnostically elusive.