Variants in BSN , encoding the presynaptic protein Bassoon, result in a novel neurodevelopmental disorder with a broad phenotypic range

Disease-causing variants in synaptic function genes are a common cause of neurodevelopmental disorders 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 comprised 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 neurodevelopmental disorders (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 new class of synaptic disorder with a broad phenotypic range across the age spectrum.