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

Journal

DOI: 10.1038/s41436-020-01020-w

Abstract

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

How to cite

APA:

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. https://dx.doi.org/10.1038/s41436-020-01020-w

MLA:

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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