Variants in BSN, encoding the presynaptic protein Bassoon, result in a distinct neurodevelopmental disorder with a...

Disease-causing variants in synaptic function genes are a common cause of neurodevelopmental disorders (NDDs) and epilepsy. Here, we describe 14 individuals with de novo disruptive variants in BSN, which encodes the presynaptic protein Bassoon. To expand the phenotypic spectrum, we identified 15 additional individuals with protein-truncating variants (PTVs) from large biobanks. Clinical features were standardized using the Human Phenotype Ontology (HPO) across all 29 individuals, which revealed common clinical characteristics including epilepsy (13/29, 45%), febrile seizures (7/29, 25%), generalized tonic-clonic seizures (5/29, 17%), and focal-onset seizures (3/29, 10%). Behavioral phenotypes were present in almost half of all individuals (14/29, 48%), which included ADHD (7/29, 25%) and autistic behavior (5/29, 17%). Additional common features included developmental delay (11/29, 38%), obesity (10/29, 34%), and delayed speech (8/29, 28%). In adults with BSN PTVs, milder features were common, suggesting phenotypic variability, including a range of individuals without obvious neurodevelopmental features (7/29, 24%). To detect gene-specific signatures, we performed association analysis in a cohort of 14,895 individuals with NDDs. A total of 66 clinical features were associated with BSN, including febrile seizures (p = 1.26e-06) and behavioral disinhibition (p = 3.39e-17). Furthermore, individuals carrying BSN variants were phenotypically more similar than expected by chance (p = 0.00014), exceeding phenotypic relatedness in 179/256 NDD-related conditions. In summary, integrating information derived from community-based gene matching and large data repositories through computational phenotyping approaches, we identify BSN variants as the cause of a synaptic disorder with a broad phenotypic range across the age spectrum.