Variants in BSN, encoding the presynaptic protein Bassoon, result in a distinct neurodevelopmental disorder with a broad phenotypic range - PubMed (original) (raw)

. 2025 Jun 5;112(6):1415-1429.

doi: 10.1016/j.ajhg.2025.04.011. Epub 2025 May 19.

Sarah M Ruggiero 2, Shiva Ganesan 2, Colin A Ellis 3, Alicia G Harrison 2, Katie R Sullivan 2, Zornitza Stark 4, Natasha J Brown 4, Sajel L Kana 5, Anabelle Tuttle 6, Jair Tenorio 7, Pablo Lapunzina 7, Julián Nevado 8, Marie T McDonald 9, Courtney Jensen 10, Patricia G Wheeler 11, Lila Stange 11, Jennifer Morrison 11, Boris Keren 12, Solveig Heide 13, Meg W Keating 14, Kameryn M Butler 14, Mike A Lyons 15, Shailly Jain 16, Mehdi Yeganeh 17, Michelle L Thompson 18, Molly Schroeder 19, Hoanh Nguyen 19, Jorge Granadillo 20, Kari M Johnston 21, Chaya N Murali 21, Katie Bosanko 22, T Andrew Burrow 22; CHOP Birth Defects Biorepository; Penn Medicine BioBank; Syreeta Morgan 23, Deborah J Watson 24, Hakon Hakonarson 24, Ingo Helbig 25

Affiliations

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

Stacy G Guzman et al. Am J Hum Genet. 2025.

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: BSN; developmental and epileptic encephalopathy; epilepsy; genetics; human phenotype ontology; longitudinal EMR analysis; neurodevelopmental disorders.

Copyright © 2025 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Figures

Figure 1

Figure 1

Overview of BSN variants identified in 29 individuals (A) Diagram of presynaptic active-zone assembly with synaptic vesicle fusion machinery proteins, showing BSN (red) as a key scaffolding protein in synaptic vesicle positioning and release. (B) BSN with variant distribution, where de novo variants (top) include both missense (blue) and protein-truncating variants (PTVs, red), while “Other” shows that inherited and unknown inheritance variants (bottom) consist of PTVs only.

Figure 2

Figure 2

Comparison of phenotypic features in BSN cohorts reveals distinct trends by age and inheritance (A) A radial plot showing phenotypic features in the overall cohort (n = 29). Radial lines reflect the frequency of specific terms within the cohort. (B–D) (B) Radial graphs displaying phenotypic feature distribution across subgroups, categorized by age and inheritance: de novo cohort (n = 14, B), PTV pediatric cohort (n = 8, C), and PTV adult cohort (n = 7, D).

Figure 3

Figure 3

Phenotypic association analysis identifies disinhibition and fatigue as key features of BSN-related disorders Volcano plot depicting the frequency of HPO terms in the BSN cohort (red, n = 29) compared to a larger reference group (blue, n = 14,893). Red dots represent terms with odds ratio (OR) >0.5 and p < 0.05, indicating significant phenotypic associations in the BSN cohort, while blue dots represent terms with a lower association in the reference cohort. Dot size reflects term frequency within the respective group.

Figure 4

Figure 4

_BSN_-related disorders have significant phenotypic resemblance in a comparison analysis of genetic and phenotypic evidence across 256 genetic etiologies implicated in NDDs Scatterplot comparing genetic and phenotypic evidence for de novo variants in BSN (red, n = 14, p = 0.00014) against 257 genetic etiologies. Each data point represents an individual gene, with point size indicating the number of individuals with de novo variants per gene. Dashed blue lines denote the significance threshold of −log10(0.05) for both axes, with genes above these thresholds shown in blue to denote statistical significance in either genetic or phenotypic evidence, while genes below the thresholds are shown in gray. Genetic evidence on the x axis reflects the statistical significance of observed de novo variants, calculated using denovolyzeR, while phenotypic evidence on the y axis represents phenotypic similarity scores generated by sim analysis (simmax), followed by permutation analysis to assess significance. This comparative approach highlights the alignment or divergence between genetic and phenotypic evidence across genes, identifying where one type of evidence deviates from the expected correlation.

Figure 5

Figure 5

The longitudinal trajectory of clinical features in 12 individuals with BSN variants highlights early neurological manifestations and broad phenotypic spectrum Distribution of key clinical features (red) over time in 12 individuals with BSN PTVs (n = 10), and de novo PTV variants (n = 2), illustrating age-related progression of features such as epilepsy (A), neurodevelopmental delays (B), behavioral phenotypes (C), and obesity (D). Phenotypic categories were manually mapped to HPO from ICD/ICD-10 codes.

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