Findings highlight value of pursuing genetic testing, including advanced sequencing methods, for accurate diagnoses
San Diego—April 9, 2025– In a manuscript published today in the American Journal of Psychiatry titled Long-Read Genome Sequencing in Clinical Psychiatry: RFX3 Haploinsufficiency in a Hospitalized Adolescent With Autism, Intellectual Disability, and Behavioral Decompensation, authors describe how they leveraged long-read genomic sequencing (LRS) to make a genetic diagnosis in a17-year-old male with autism spectrum disorder, intellectual disability, and acute behavioral decompensation that would not have been possible by standard methods. Through the use of LRS, a cutting-edge technology that reads extended stretches of DNA in a single pass, enabling more accurate detection of complicated genetic changes, authors describe a complex rearrangement that resulted in inactivation of the RFX3 gene. The resulting clinical diagnosis of RFX3 haplo-insufficiency syndrome, which has previously been associated with autism spectrum disorder (ASD) and intellectual impairment, was not possible with the conventional technology that is currently used in clinical sequencing.
During the patient’s psychiatric hospitalization, he exhibited a range of severe symptoms, including psychosis, depression, anxiety, and catatonia. His legal guardians provided consent to enroll him in the authors’ study “Mental Health Crises in Youth with Intellectual and Developmental Disabilities.”
Standard clinical genetic testing with short-read whole-genome sequencing (WGS) initially revealed a duplication on the RFX3 gene and another larger duplication in an adjacent gene. Sequencing parental samples determined inheritance of the duplicated regions, yet it remained unclear whether there was some additional genomic change between the two duplications that was not detectable by WGS. The authors then decided to pursue LRS, which has been shown to detect more genomic structural variations compared to short-read sequencing. Authors were able to conclude that one of the parents did not simply have an RFX3 duplication, as originally thought from WGS, but in fact had a complex structural rearrangement that included both deletions and duplications of adjoining regions of DNA, ultimately resulting in RFX3 loss-of-function and a diagnosis of RFX3 haplo-insufficiency syndrome.
“Genetic testing has historically played a limited role in clinical psychiatry,” said Aaron D. Besterman, MD, Clinical Investigator at Rady Children’s Institute for Genomic Medicine and a study author. “However, as our understanding of the genetic architecture of psychiatric disorders continues to expand, mental health clinicians will increasingly need to have basic proficiency in medical genetics and be aware of when genetic testing is indicated and how it may impact their patients.”
Authors also observed that, while LRS should not currently be considered a first-line genetic test, it should be considered in cases where traditional genetic tests, including WGS, fail to identify a causative variant but clinical suspicion for a genetic cause remains high or a variant of interest is detected but cannot be elucidated by other means.
“Structural mutations in the genome can often be more complex than they first appear,” said Jonathan Sebat, Ph.D, Director of the Verge Center at the University of California, San Diego, and a coauthor of the study. “LRS allowed us to unravel the functional consequence of the mutation, which could not be determined by standard genome sequencing. New long read sequencing holds great promise as a potential first-line comprehensive genetic test that can detect a wide variety of genetic variants, large and small, however, the cost remains a barrier to widespread use.”
The authors noted that this case highlights other potential benefits of performing genetic testing during inpatient psychiatric admissions, as was done with the patient described in the paper, including the potential benefit of greatly expediting a genetic workup for an in-need population with many barriers to care and facilitating direct access to inpatient genetic services for mental health clinicians seeking additional guidance.
Article link: https://doi.org/10.1176/appi.ajp.20240471
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About Rady Children’s Institute for Genomic Medicine
Founded in 2014, Rady Children’s Institute for Genomic Medicine (RCIGM) pioneered a medical revolution through its record-breaking rapid Whole Genome Sequencing™ test that endeavored to end the diagnostic odyssey for neonatal and pediatric rare disease patients and their families. Now the Institute is moving to end the therapeutic odyssey by pinpointing the root cause of previously unidentified conditions. RCIGM scientists and innovators work on translating discoveries into therapies and tools to guide clinical decision-making for providers at the bedside. The Institute’s research into the use of rWGS® in a clinical NICU setting continues to lay the groundwork for systemic changes in pediatric healthcare. RCIGM is a non-profit research organization embedded within Rady Children’s Hospital San Diego, Learn more at RadyGenomics.org and follow us LinkedIn.