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The presynaptic scaffold protein Bassoon, encoded by BSN, organizes active zone assembly and neurotransmitter release. Emerging evidence implicates BSN variants in a spectrum of epilepsy phenotypes, ranging from early‐onset febrile seizures to focal and generalized epilepsies.
In a cohort of 313 trios with unexplained epilepsy, four compound heterozygous and one cosegregating heterozygous missense BSN variants were identified in five unrelated families, with a significantly higher variant frequency in cases versus controls (PMID:36600631).
Additional screening via a gene‐matching platform uncovered two de novo heterozygous nonsense variants and one cosegregating heterozygous missense variant in three unrelated probands, all absent from gnomAD, supporting both recessive and dominant mechanisms in epilepsy (PMID:36600631).
In a larger neurodevelopmental cohort, 15 individuals with BSN protein-truncating variants were identified, of whom 13/29 (45%) presented with epilepsy, including febrile seizures, generalized tonic-clonic, and focal-onset seizures, further consolidating BSN’s role in epilepsy pathogenesis (PMID:40393460).
The variant spectrum comprises at least eight missense substitutions (e.g., c.418C>T (p.Arg140Trp)) and multiple truncating alleles clustering in C-terminal scaffolding domains. Protein modelling demonstrated hydrogen bond alterations in at least one allele of each compound heterozygous pair, consistent with a loss-of-function effect (PMID:36600631).
Collectively, segregation data, de novo occurrences, and functional modelling assign a Strong clinical validity to the BSN-epilepsy association. BSN-related epilepsy follows both autosomal recessive and de novo autosomal dominant patterns. Key take-home: BSN variant screening enhances diagnostic precision and informs management in epilepsy.
Gene–Disease AssociationStrong21 unrelated probands across multiple studies, including 5 families with segregation, de novo occurrences, and functional concordance Genetic EvidenceStrong21 probands with 12 unique BSN variants, including compound heterozygous, de novo truncating, and missense changes Functional EvidenceModerateProtein modelling showed hydrogen bond alterations in missense alleles, supporting loss‐of‐function in active zone scaffolding domains |