Newly Identified Gene Associated with Neurodevelopmental Conditions and Epilepsy Enhances Diagnostic Capabilities

Researchers at Children's Hospital of Philadelphia (CHOP) have discovered a novel gene linked to neurodevelopmental disorders and epilepsy, opening new pathways for diagnosis and potentially targeted treatments. Published in the American Journal of Human Genetics, this groundbreaking study utilized extensive genetic datasets, advanced computational methods, and community-based gene matching techniques.

The focus was on the BSN gene, which is prominently expressed in the brain and encodes the Bassoon protein. This protein is essential for supporting synapses, the crucial structures that enable communication between brain cells. Interestingly, the name 'Bassoon' derives from its resemblance to a musical instrument. Variations in the BSN gene have been rarely reported in clinical cases, despite its suspected role in brain health.

The impetus for this research stemmed from observations within the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP, where two pediatric patients with epilepsy exhibited de novo variants in the BSN gene—these variants were not inherited but occurred spontaneously.

"These findings prompted us to investigate further, and we identified additional patients with similar genetic variations and clinical features," explained Sarah M. Ruggiero, a genetic counselor at ENGIN. To deepen understanding, the team integrated data from multiple biobanks, including the Penn Medicine BioBank and CHOP's Birth Defects Biorepository, utilizing the Human Phenotype Ontology (HPO) to standardize and analyze clinical information.

The study identified 29 individuals with disruptive BSN variants causing non-functional proteins. The most common symptom among these patients was epilepsy, affecting 45%, with other recurrent features including febrile seizures, generalized tonic-clonic seizures, and focal onset seizures. Behavioral issues such as ADHD and autism spectrum behaviors, along with developmental delays, obesity, and speech delays, were also prevalent.

Comparative analysis revealed that the genetic and phenotypic pattern of this disorder is distinct from other neurodevelopmental conditions, emphasizing its uniqueness.

"Given the rarity of this genetic disorder, large-scale data analyses are vital for understanding its full spectrum and for discovering potential biomarkers for clinical trials," stated senior author Ingo Helbig, MD. This research paves the way for improved diagnosis, better understanding of the disorder’s natural history, and exploration of personalized treatment options.

This study underscores the importance of integrating genomic data, clinical features, and biobanking resources to uncover and characterize new neurodevelopmental disorders, ultimately enhancing patient care and genetic counseling.