Children’s Hospital of Philadelphia Researchers Identify Novel Gene Associated with Neurodevelopmental Disorders and Epilepsy

Researchers from Children’s Hospital of Philadelphia (CHOP) identified a novel gene associated with neurodevelopmental disorders and epilepsy. The study, recently published online by the American Journal of Human Genetics, leveraged large data depositories, state-of-the-art computational techniques and community-based gene matching to identify this new gene, which is a critical early step in improving diagnosis and eventually developing new treatment methods.

The BSN gene is highly expressed in the brain and encodes for the protein Bassoon, which helps support the synapses that allow brain cells to send messages between cells. The gene’s unusual name comes from the stick-like protein’s resemblance to the musical instrument of the same name. While BSN has been linked to various brain disorders, few clinical cases with variants of the BSN gene have been reported. 

The study was prompted by the team at the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP after researchers discovered two pediatric patients with epilepsy had variants in the BSN gene.

“These two patients had de novo variants of the BSN gene, meaning that they did not inherit these variants from either parent,” said study co-author Sarah M. Ruggiero, a licensed genetic counselor with ENGIN at CHOP, who first saw the pattern of BSN variants in ENGIN patients. “With this new information, we tried to see what else we could learn about these variants and if any other patients with these symptoms had these variants, and eventually, we identified additional patients, which we’re reporting for the first time.”

To explore BSN’s role in neurodevelopmental disorders, researchers with ENGIN and the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) at CHOP and Penn harnessed data and technology from the Penn Medicine BioBank, the CHOP Birth Defects Biorepository, and the Center for Applied Genomics (CAG), all groups who have collected biological samples from patients and other family members that can be utilized for research studies. This is the first study to integrate data collected from the CHOP Birth Defects Biorepository.

“The goal of the Birth Defects Biorepository is to provide a sustainable resource to support investigations like this one into the etiologies of birth defects in a way that can help us understand long-term outcomes for these children and help advance the development of personalized medicine,” said J. William Gaynor, MD, Director of the Long-term Follow-up Program in the Cardiac Center at CHOP and as the Co-Principal Investigator of the Birth Defects Biorepository. “The genomic and phenotypic datasets provided to the investigators for this project are examples of the kinds of resources we hope to make available for other birth defects that require deeper levels of investigation.”

In this study, the researchers employed the Human Phenotype Ontology (HPO), a dictionary of more than 15,000 terms that standardizes clinical information from electronic medical records, as well as resources from the Center for Applied Genomics, to analyze the large data sets from the biobanks. The study describes 29 total individuals with disruptive variants of BSN that cause non-functional proteins. Across all patients, epilepsy was the most common symptom (45%), followed by febrile seizures (25%) generalized tonic-clonic seizures (17%) and focal onset seizures (10%). Behavioral features such as ADHD (25%) and autistic behavior (17%) were also observed, and additional symptoms such as developmental delay (38%), obesity (34%) and delayed speech (28%) were also noted. When compared to other individuals with neurodevelopmental disorders, these features made BSN stick out as a disorder with a unique and distinct pattern. 

“With a novel genetically driven neurodevelopmental disorder that is relatively rare, there is no way for us to do a prospective natural history on a small group of patients,” said senior study author Ingo Helbig, MD, director of Genomic Science and co-director of ENGIN at CHOP. “By doing this big data sweep, we have critical information that allows us to understand the landscape of the disease and how many patients may be affected and help lead us to biomarkers for clinical trials.”

This study was supported by Perelman School of Medicine at University of Pennsylvania, a gift from the Smilow family, and the National Center for Advancing Translational Sciences of the National Institutes of Health under CTSA award number UL1TR001878. The CHOP Birth Defects Biorepository (BDB) is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001878. Individual 3 was identified as part of the Acute Care Genomics study research study, funded by the Australian Government’s Medical Research Future Fund grant number GHFM76747. We acknowledge the use of data from the Deciphering Developmental Disorders (DDD) project. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund grant number HICF-1009- 003. This study makes use of DECIPHER, which is funded by Wellcome grant number WT223718/Z/21/Z. The study was also supported by the National Institute for Neurological Disorders and Stroke grants R01 NS131512, R01 NS127830 and U24 NS120854 and the Hartwell Foundation Individual Biomedical Research Award.

Guzman et al, “Variants in BSN, encoding the presynaptic protein Bassoon, result in a distinct neurodevelopmental disorder with a broad phenotypic range.” Am J Human Genet. Online May 16, 2025. DOI: 10.1016/j.ajhg.2025.04.011.