Language

English

Publication Date

6-5-2025

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2025.04.011

PMID

40393460

PMCID

PMC12256794

PubMedCentral® Posted Date

5-19-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Male, Female, Neurodevelopmental Disorders, Phenotype, Child, Nerve Tissue Proteins, Adult, Child, Preschool, Adolescent, Young Adult, Middle Aged, Seizures, Febrile, Epilepsy, epilepsy, genetics, developmental and epileptic encephalopathy, BSN, neurodevelopmental disorders, longitudinal EMR analysis, human phenotype ontology

Published Open-Access

yes

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