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Klöckner, C.* ; Sticht, H.* ; Zacher, P.* ; Popp, B.* ; Babcock, H.E.* ; Bakker, D.P.* ; Barwick, K.* ; Bonfert, M.V.* ; Bönnemann, C.G.* ; Brilstra, E.H.* ; Chung, W.K.* ; Clarke, A.J.* ; Devine, P.* ; Donkervoort, S.* ; Fraser, J.L.* ; Friedman, J.* ; Gates, A.* ; Ghoumid, J.* ; Hobson, E.* ; Horvath, G.* ; Keller-Ramey, J.* ; Keren, B.* ; Kurian, M.A.* ; Lee, V.* ; Leppig, K.A.* ; Lundgren, J.* ; McDonald, M.T.* ; McTague, A.* ; Mefford, H.C.* ; Mignot, C.* ; Mikati, M.A.* ; Nava, C.* ; Raymond, F.L.* ; Sampson, J.R.* ; Sanchis-Juan, A.* ; Shashi, V.* ; Shieh, J.T.C.* ; Shinawi, M.* ; Slavotinek, A.* ; Stödberg, T.* ; Stong, N.* ; Sullivan, J.A.* ; Taylor, A.C.* ; Toler, T.L.* ; van den Boogaard, M.J.* ; van der Crabben, S.N.* ; van Gassen, K.L.I.* ; van Jaarsveld, R.H.* ; Van Ziffle, J.* ; Wadley, A.F.* ; Wagner, M. ; Wigby, K.* ; Wortmann, S.B.* ; Zarate, Y.A.* ; Møller, R.S.* ; Lemke, J.R.* ; Platzer, K.*

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

Genet. Med., DOI: 10.1038/s41436-020-01020-w (2020)
Postprint DOI PMC
Open Access Green
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.”.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mutations; Protein
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Journal Genetics in Medicine
Publisher Lippincott Williams & Wilkins
Publishing Place Baltimore, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants National Heart, Lung and Blood Institute
Genome Alberta
Ontario Research Fund
Canadian Institutes of Health Research
Ontario Genomics Institute
Genome Canada
Duke University Health System
NIHR
Cambridge Biomedical Research Centre
National Institute for Health Research (NIHR) GOSH BRC
JPB Foundation
Genome British Columbia
BC Children's Hospital Foundation
National Eye Institute
National Human Genome Research Institute
NIH National Institute of Neurological Disorders and Stroke
National Human Genome Research Institute of the National Institutes of Health
Lundbeck Foundation
Wellcome Trust
Children's Hospital of Eastern Ontario Foundation
Genome Quebec
BC Provincial Health Services Authority
BC Children's Hospital Research Institute
SFARI