De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

doi:10.1038/s41436-020-01020-w

. 2021 Apr;23(4):653-660.

doi: 10.1038/s41436-020-01020-w. Epub 2020 Dec 10.

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Chiara Klöckner¹, Heinrich Sticht², Pia Zacher³, Bernt Popp¹, Holly E Babcock⁴, Dewi P Bakker⁵, Katy Barwick⁶, Michaela V Bonfert⁷, Carsten G Bönnemann⁸, Eva H Brilstra⁹; Care4Rare Canada Consortium; Wendy K Chung¹⁰, Angus J Clarke¹¹, Patrick Devine¹², Sandra Donkervoort⁸, Jamie L Fraser¹³, Jennifer Friedman^{14

15}, Alyssa Gates¹⁶, Jamal Ghoumid¹⁷, Emma Hobson¹⁸, Gabriella Horvath¹⁹, Jennifer Keller-Ramey²⁰, Boris Keren²¹, Manju A Kurian⁶, Virgina Lee²², Kathleen A Leppig¹⁶, Johan Lundgren²³, Marie T McDonald²⁴, Heather M McLaughlin²⁵, Amy McTague⁶, Heather C Mefford²⁶, Cyril Mignot²⁷, Mohamad A Mikati²⁸, Caroline Nava²⁹, F Lucy Raymond^{30

31}, Julian R Sampson¹¹, Alba Sanchis-Juan^{30

32}, Vandana Shashi²⁴, Joseph T C Shieh^{33

34}, Marwan Shinawi³⁵, Anne Slavotinek³³, Tommy Stödberg³⁶, Nicholas Stong³⁷, Jennifer A Sullivan²⁴, Ashley C Taylor³⁸, Tomi L Toler³⁵, Marie-José van den Boogaard⁹, Saskia N van der Crabben³⁹, Koen L I van Gassen⁹, Richard H van Jaarsveld⁹, Jessica Van Ziffle¹², Alexandrea F Wadley⁴⁰, Matias Wagner⁴¹, Kristen Wigby⁴², Saskia B Wortmann^{43

44}, Yuri A Zarate⁴⁵, Rikke S Møller^{46

47}, Johannes R Lemke¹, Konrad Platzer⁴⁸

Affiliations

¹ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
² Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
³ The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany.
⁴ Rare Disease Institute, Children's National Hospital, Washington, DC, USA.
⁵ Department of Child Neurology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
⁶ Institute of Child Health, University Collge London, London, UK.
⁷ Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, LMU - University Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
⁸ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁰ Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA.
¹¹ Division of Cancer & Genetics, School of Medicine, Cardiff University, Wales, UK.
¹² Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
¹³ Rare Disease Institute, Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
¹⁴ Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children's Hospital, San Diego, CA, USA.
¹⁵ Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
¹⁶ Department of Genetic Services, Kaiser Permanente Washington, Seattle, WA, USA.
¹⁷ Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.
¹⁸ Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK.
¹⁹ Department of Pediatrics, Division of Biochemical Diseases, University of British Columbia, Vancouver, Canada.
²⁰ GeneDx, Gaithersburg, MD, USA.
²¹ APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France.
²² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
²³ Institute of Clinical Sciences, Skane University Hospital, Lund, Sweden.
²⁴ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
²⁵ Invitae Corporation, San Francisco, CA, USA.
²⁶ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
²⁷ Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et Hôpital Trousseau, APHP, Sorbonne Université, Paris, France.
²⁸ Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
²⁹ Sorbonne University, Paris Brain Institute, Inserm U1127, CNRS UMR 7225, AP-HP, Pitié Salpêtrière Hospital, Department of Genetics, Paris, France.
³⁰ NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
³¹ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
³² Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.
³³ Division of Medical Genetics, University of California, San Francisco, San Francisco, CA, USA.
³⁴ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
³⁵ Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
³⁶ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
³⁷ Institute for Genomic Medicine, Columbia University, New York, NY, USA.
³⁸ Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁹ Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
⁴⁰ University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴¹ Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany.
⁴² Department of Pediatrics, Division of Genetics, University of California, San Diego and Rady Children's Hospital-San Diego, San Diego, CA, USA.
⁴³ Amalia Children's Hospital, Radboud University Nijmegen, Nijmegen, The Netherlands.
⁴⁴ University Childrens Hospital, Paracelsus Medical University, Salzburg, Austria.
⁴⁵ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
⁴⁶ Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
⁴⁷ Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
⁴⁸ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. konrad.platzer@medizin.uni-leipzig.de.

PMID: 33299146
DOI: 10.1038/s41436-020-01020-w

Free article

De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

Chiara Klöckner et al. Genet Med. 2021 Apr.

Free article

. 2021 Apr;23(4):653-660.

doi: 10.1038/s41436-020-01020-w. Epub 2020 Dec 10.

Authors

Affiliations

¹ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
² Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
³ The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany.
⁴ Rare Disease Institute, Children's National Hospital, Washington, DC, USA.
⁵ Department of Child Neurology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
⁶ Institute of Child Health, University Collge London, London, UK.
⁷ Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children's Hospital, LMU - University Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
⁸ Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁰ Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA.
¹¹ Division of Cancer & Genetics, School of Medicine, Cardiff University, Wales, UK.
¹² Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
¹³ Rare Disease Institute, Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
¹⁴ Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children's Hospital, San Diego, CA, USA.
¹⁵ Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
¹⁶ Department of Genetic Services, Kaiser Permanente Washington, Seattle, WA, USA.
¹⁷ Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France.
¹⁸ Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, UK.
¹⁹ Department of Pediatrics, Division of Biochemical Diseases, University of British Columbia, Vancouver, Canada.
²⁰ GeneDx, Gaithersburg, MD, USA.
²¹ APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France.
²² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
²³ Institute of Clinical Sciences, Skane University Hospital, Lund, Sweden.
²⁴ Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
²⁵ Invitae Corporation, San Francisco, CA, USA.
²⁶ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
²⁷ Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et Hôpital Trousseau, APHP, Sorbonne Université, Paris, France.
²⁸ Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
²⁹ Sorbonne University, Paris Brain Institute, Inserm U1127, CNRS UMR 7225, AP-HP, Pitié Salpêtrière Hospital, Department of Genetics, Paris, France.
³⁰ NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
³¹ Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
³² Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, UK.
³³ Division of Medical Genetics, University of California, San Francisco, San Francisco, CA, USA.
³⁴ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
³⁵ Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
³⁶ Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
³⁷ Institute for Genomic Medicine, Columbia University, New York, NY, USA.
³⁸ Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
³⁹ Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
⁴⁰ University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁴¹ Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany.
⁴² Department of Pediatrics, Division of Genetics, University of California, San Diego and Rady Children's Hospital-San Diego, San Diego, CA, USA.
⁴³ Amalia Children's Hospital, Radboud University Nijmegen, Nijmegen, The Netherlands.
⁴⁴ University Childrens Hospital, Paracelsus Medical University, Salzburg, Austria.
⁴⁵ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
⁴⁶ Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
⁴⁷ Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
⁴⁸ Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany. konrad.platzer@medizin.uni-leipzig.de.

PMID: 33299146
DOI: 10.1038/s41436-020-01020-w

Erratum in

Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy.
Klöckner C, Sticht H, Zacher P, Popp B, Babcock HE, Bakker DP, Barwick K, Bonfert MV, Bönnemann CG, Brilstra EH; Care4Rare Canada Consortium; Chung WK, Clarke AJ, Devine P, Donkervoort S, Fraser JL, Friedman J, Gates A, Ghoumid J, Hobson E, Horvath G, Keller-Ramey J, Keren B, Kurian MA, Lee V, Leppig KA, Lundgren J, McDonald MT, McLaughlin HM, McTague A, Mefford HC, Mignot C, Mikati MA, Nava C, Raymond FL, Sampson JR, Sanchis-Juan A, Shashi V, Shieh JTC, Shinawi M, Slavotinek A, Stödberg T, Stong N, Sullivan JA, Taylor AC, Toler TL, van den Boogaard MJ, van der Crabben SN, van Gassen KLI, van Jaarsveld RH, Van Ziffle J, Wadley AF, Wagner M, Wigby K, Wortmann SB, Zarate YA, Møller RS, Lemke JR, Platzer K. Klöckner C, et al. Genet Med. 2021 Apr;23(4):796. doi: 10.1038/s41436-020-01090-w. Genet Med. 2021. PMID: 33686260 No abstract available.

Abstract

Purpose: This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals.

Methods: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.

Results: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.

Conclusion: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."

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References

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[1] Rizo, J. & Xu, J. The synaptic vesicle release machinery. Annu. Rev. Biophys. 44, 339–367, https://doi.org/10.1146/annurev-biophys-060414-034057 (2015). - DOI - PubMed

[2] Rizo, J. & Xu, J. The synaptic vesicle release machinery. Annu. Rev. Biophys. 44, 339–367, https://doi.org/10.1146/annurev-biophys-060414-034057 (2015). - DOI - PubMed

[3] Jahn, R. & Fasshauer, D. Molecular machines governing exocytosis of synaptic vesicles. Nature. 490, 201–207, https://doi.org/10.1038/nature11320 (2012). - DOI - PubMed - PMC

[4] Jahn, R. & Fasshauer, D. Molecular machines governing exocytosis of synaptic vesicles. Nature. 490, 201–207, https://doi.org/10.1038/nature11320 (2012). - DOI - PubMed - PMC

[5] Ramakrishnan, N. A., Drescher, M. J. & Drescher, D. G. The SNARE complex in neuronal and sensory cells. Mol. Cell. Neurosci. 50, 58–69, https://doi.org/10.1016/j.mcn.2012.03.009 (2012). - DOI - PubMed - PMC

[6] Ramakrishnan, N. A., Drescher, M. J. & Drescher, D. G. The SNARE complex in neuronal and sensory cells. Mol. Cell. Neurosci. 50, 58–69, https://doi.org/10.1016/j.mcn.2012.03.009 (2012). - DOI - PubMed - PMC

[7] Hepp, R. & Langley, K. SNAREs during development. Cell Tissue Res. 305, 247–253, https://doi.org/10.1007/s004410100359 (2001). - DOI - PubMed

[8] Hepp, R. & Langley, K. SNAREs during development. Cell Tissue Res. 305, 247–253, https://doi.org/10.1007/s004410100359 (2001). - DOI - PubMed

[9] Han, J., Pluhackova, K. & Böckmann, R. A. The multifaceted role of SNARE proteins in membrane fusion. Front. Physiol. 8, 5, https://doi.org/10.3389/fphys.2017.00005 (2017). - DOI - PubMed - PMC

[10] Han, J., Pluhackova, K. & Böckmann, R. A. The multifaceted role of SNARE proteins in membrane fusion. Front. Physiol. 8, 5, https://doi.org/10.3389/fphys.2017.00005 (2017). - DOI - PubMed - PMC

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De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

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De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy

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