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

doi:10.1016/j.ajhg.2025.04.011

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

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

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

Stacy G Guzman¹, Sarah M Ruggiero², Shiva Ganesan², Colin A Ellis³, Alicia G Harrison², Katie R Sullivan², Zornitza Stark⁴, Natasha J Brown⁴, Sajel L Kana⁵, Anabelle Tuttle⁶, Jair Tenorio⁷, Pablo Lapunzina⁷, Julián Nevado⁸, Marie T McDonald⁹, Courtney Jensen¹⁰, Patricia G Wheeler¹¹, Lila Stange¹¹, Jennifer Morrison¹¹, Boris Keren¹², Solveig Heide¹³, Meg W Keating¹⁴, Kameryn M Butler¹⁴, Mike A Lyons¹⁵, Shailly Jain¹⁶, Mehdi Yeganeh¹⁷, Michelle L Thompson¹⁸, Molly Schroeder¹⁹, Hoanh Nguyen¹⁹, Jorge Granadillo²⁰, Kari M Johnston²¹, Chaya N Murali²¹, Katie Bosanko²², T Andrew Burrow²²; CHOP Birth Defects Biorepository; Penn Medicine BioBank; Syreeta Morgan²³, Deborah J Watson²⁴, Hakon Hakonarson²⁴, Ingo Helbig²⁵

Affiliations

¹ Department of Biochemistry, Biophysics, and Chemical Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
² The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; Epilepsy and Neurodevelopmental Disorders Center (ENDD), Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Epilepsy and Neurodevelopmental Disorders Center (ENDD), Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Australian Genomics, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
⁵ Division of Clinical Genetics, Genomics, and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA.
⁶ GeneDx, Gaithersburg, MD, USA.
⁷ Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IDIPAZ, 28046 Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain.
⁸ Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IDIPAZ, 28046 Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain; ERN-ITHACA-European Reference Network, Madrid, Spain.
⁹ Department of Pediatrics, Duke University Medical Center, Duke University, Durham, NC, USA.
¹⁰ Children's Services, Duke University Health Center, Duke University, Durham, NC, USA.
¹¹ Pediatric Genetics Specialty Practice, Arnold Palmer Hospital for Children, Orlando, FL, USA.
¹² Department of Genetics, La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
¹³ Cytogenetics Department, Cochin Hospital, Assistance Publique des Hôpitaux de Paris, Sorbonne Paris Cité, Paris Descartes University, Medical School, Paris, France.
¹⁴ Greenwood Genetics Center, Greenwood, SC, USA.
¹⁵ Greenwood Genetics Center, Greenwood, SC, USA; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State Universitygrid.47894.36, Fort Collins, CO, USA.
¹⁶ Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
¹⁷ Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Centre Hospitalier Universitaire de Québec, Centre Mère-Enfant Soleil Université Laval, Québec City, QC, Canada.
¹⁸ Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Molecular and Human Genetics, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
²⁰ Division of Molecular and Human Genetics, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
²¹ Department of Genetics and Metabolism, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
²² Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
²³ Center for Applied Genomics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁴ Center for Applied Genomics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Biochemistry, Biophysics, and Chemical Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; Epilepsy and Neurodevelopmental Disorders Center (ENDD), Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: ihelbig@email.chop.edu.

PMID: 40393460
PMCID: PMC12256794 (available on 2025-12-05)
DOI: 10.1016/j.ajhg.2025.04.011

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.

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

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

Authors

Affiliations

¹ Department of Biochemistry, Biophysics, and Chemical Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
² The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; Epilepsy and Neurodevelopmental Disorders Center (ENDD), Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Epilepsy and Neurodevelopmental Disorders Center (ENDD), Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
⁴ Australian Genomics, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
⁵ Division of Clinical Genetics, Genomics, and Metabolism, Nicklaus Children's Hospital, Miami, FL, USA.
⁶ GeneDx, Gaithersburg, MD, USA.
⁷ Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IDIPAZ, 28046 Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain.
⁸ Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz-IDIPAZ, 28046 Madrid, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain; ERN-ITHACA-European Reference Network, Madrid, Spain.
⁹ Department of Pediatrics, Duke University Medical Center, Duke University, Durham, NC, USA.
¹⁰ Children's Services, Duke University Health Center, Duke University, Durham, NC, USA.
¹¹ Pediatric Genetics Specialty Practice, Arnold Palmer Hospital for Children, Orlando, FL, USA.
¹² Department of Genetics, La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
¹³ Cytogenetics Department, Cochin Hospital, Assistance Publique des Hôpitaux de Paris, Sorbonne Paris Cité, Paris Descartes University, Medical School, Paris, France.
¹⁴ Greenwood Genetics Center, Greenwood, SC, USA.
¹⁵ Greenwood Genetics Center, Greenwood, SC, USA; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State Universitygrid.47894.36, Fort Collins, CO, USA.
¹⁶ Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
¹⁷ Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Centre Hospitalier Universitaire de Québec, Centre Mère-Enfant Soleil Université Laval, Québec City, QC, Canada.
¹⁸ Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA; Division of Molecular and Human Genetics, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
²⁰ Division of Molecular and Human Genetics, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
²¹ Department of Genetics and Metabolism, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
²² Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
²³ Center for Applied Genomics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
²⁴ Center for Applied Genomics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Biochemistry, Biophysics, and Chemical Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA; Epilepsy and Neurodevelopmental Disorders Center (ENDD), Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: ihelbig@email.chop.edu.

PMID: 40393460
PMCID: PMC12256794 (available on 2025-12-05)
DOI: 10.1016/j.ajhg.2025.04.011

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.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

Variants in BSN, encoding the presynaptic protein Bassoon, result in a novel neurodevelopmental disorder with a broad phenotypic range.
Guzman SG, Ruggiero SM, Ganesan S, Ellis CA, Harrison AG, Sullivan KR, Stark Z, Brown NJ, Kana SL, Tuttle A, Tenorio J, Lapunzina P, Nevado J, McDonald MT, Jensen C, Wheeler PG, Stange L, Morrison J, Keren B, Heide S, Keating MW, Butler KM, Lyons MA, Jain S, Yeganeh M, Thompson ML, Schroeder M, Nguyen H, Granadillo J, Johnston KM, Murali CN, Bosanko K, Burrow TA; CHOP Birth Defects Biorepository, Penn Medicine Biobank; Morgan S, Watson DJ, Hakonarson H, Helbig I. Guzman SG, et al. medRxiv [Preprint]. 2025 Feb 12:2025.02.10.25321755. doi: 10.1101/2025.02.10.25321755. medRxiv. 2025. Update in: Am J Hum Genet. 2025 Jun 5;112(6):1415-1429. doi: 10.1016/j.ajhg.2025.04.011. PMID: 39990563 Free PMC article. Updated. Preprint.

References

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[1] Garner C.C., Kindler S., Gundelfinger E.D. Molecular determinants of presynaptic active zones. Curr. Opin. Neurobiol. 2000;10:321–327. doi: 10.1016/s0959-4388(00)00093-3. - DOI - PubMed

[2] Garner C.C., Kindler S., Gundelfinger E.D. Molecular determinants of presynaptic active zones. Curr. Opin. Neurobiol. 2000;10:321–327. doi: 10.1016/s0959-4388(00)00093-3. - DOI - PubMed

[3] Schoch S., Gundelfinger E.D. Molecular organization of the presynaptic active zone. Cell Tissue Res. 2006;326:379–391. doi: 10.1007/s00441-006-0244-y. - DOI - PubMed

[4] Schoch S., Gundelfinger E.D. Molecular organization of the presynaptic active zone. Cell Tissue Res. 2006;326:379–391. doi: 10.1007/s00441-006-0244-y. - DOI - PubMed

[5] Dieck S., Sanmartí-Vila L., Langnaese K., Richter K., Kindler S., Soyke A., Wex H., Smalla K.-H., Kämpf U., Fränzer J.-T., et al. Bassoon, a Novel Zinc-finger CAG/Glutamine-repeat Protein Selectively Localized at the Active Zone of Presynaptic Nerve Terminals. J. Cell Biol. 1998;142:499–509. doi: 10.1083/jcb.142.2.499. - DOI - PMC - PubMed

[6] Dieck S., Sanmartí-Vila L., Langnaese K., Richter K., Kindler S., Soyke A., Wex H., Smalla K.-H., Kämpf U., Fränzer J.-T., et al. Bassoon, a Novel Zinc-finger CAG/Glutamine-repeat Protein Selectively Localized at the Active Zone of Presynaptic Nerve Terminals. J. Cell Biol. 1998;142:499–509. doi: 10.1083/jcb.142.2.499. - DOI - PMC - PubMed

[7] Gundelfinger E.D., Reissner C., Garner C.C. Role of Bassoon and Piccolo in Assembly and Molecular Organization of the Active Zone. Front. Synaptic Neurosci. 2015;7:19. doi: 10.3389/fnsyn.2015.00019. - DOI - PMC - PubMed

[8] Gundelfinger E.D., Reissner C., Garner C.C. Role of Bassoon and Piccolo in Assembly and Molecular Organization of the Active Zone. Front. Synaptic Neurosci. 2015;7:19. doi: 10.3389/fnsyn.2015.00019. - DOI - PMC - PubMed

[9] Winter C., tom Dieck S., Boeckers T.M., Bockmann J., Kämpf U., Sanmartí-Vila L., Langnaese K., Altrock W., Stumm M., Soyke A., et al. The presynaptic cytomatrix protein Bassoon: sequence and chromosomal localization of the human BSN gene. Genomics. 1999;57:389–397. doi: 10.1006/geno.1999.5788. - DOI - PubMed

[10] Winter C., tom Dieck S., Boeckers T.M., Bockmann J., Kämpf U., Sanmartí-Vila L., Langnaese K., Altrock W., Stumm M., Soyke A., et al. The presynaptic cytomatrix protein Bassoon: sequence and chromosomal localization of the human BSN gene. Genomics. 1999;57:389–397. doi: 10.1006/geno.1999.5788. - DOI - PubMed

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

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

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