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

Kloeckner C, Sticht H, Zacher P, Popp B, Babcock HE, Bakker DP, Barwick K, Bonfert M, Bonnemann CG, Brilstra EH, 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, 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, Stodberg T, Stong N, Sullivan JA, Taylor AC, Toler TL, Van Den Boogaard MJ, Van Der Crabben SN, Van Gassen KL, Van Jaarsveld RH, Van Ziffle J, Wadley AF, Wagner M, Wigby K, Wortmann SB, Zarate YA, Moller RS, Lemke JR, Platzer K (2020)

Publication Type: Journal article

Publication year: 2020


DOI: 10.1038/s41436-020-01020-w


Purpose: This study aimsed 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.”.

Authors with CRIS profile

Involved external institutions

Universität Leipzig DE Germany (DE) Kleinwachau - Sächsisches Epilepsiezentrum Radeberg gGmbH DE Germany (DE) Children’s National Health System US United States (USA) (US) University of Amsterdam NL Netherlands (NL) University College London (UCL) GB United Kingdom (GB) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) National Institute of Neurological Disorders and Stroke (NINDS) US United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Columbia University US United States (USA) (US) Cardiff University GB United Kingdom (GB) University of California, San Diego US United States (USA) (US) University of British Columbia CA Canada (CA) GeneDX US United States (USA) (US) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière FR France (FR) University of California San Francisco (UCSF) US United States (USA) (US) Kaiser Permanente US United States (USA) (US) Skåne University Hospital / Skånes universitetssjukhus SE Sweden (SE) Duke University US United States (USA) (US) University of Washington US United States (USA) (US) University of Paris 4 - Paris-Sorbonne / Université paris IV Paris-Sorbonne FR France (FR) Cambridge University Hospital GB United Kingdom (GB) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) FR France (FR) Chapel Allerton Hospital GB United Kingdom (GB) Washington University in St. Louis US United States (USA) (US) Karolinska Institute SE Sweden (SE) University of Oklahoma US United States (USA) (US) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Radboud University Nijmegen NL Netherlands (NL) University of Arkansas US United States (USA) (US) University of Southern Denmark / Syddansk Universitet DK Denmark (DK)

How to cite


Kloeckner, C., Sticht, H., Zacher, P., Popp, B., Babcock, H.E., Bakker, D.P.,... Platzer, K. (2020). De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy. Genetics in Medicine.


Kloeckner, Chiara, et al. "De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy." Genetics in Medicine (2020).

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