Journal
GENETICS IN MEDICINE
Volume 23, Issue 4, Pages 653-660Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-020-01020-w
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Categories
Funding
- SFARI
- JPB Foundation
- National Institute for Health Research (NIHR) GOSH BRC
- Cambridge Biomedical Research Centre
- NIHR [RG65966]
- Duke University Health System
- Genome Canada
- Ontario Genomics Institute [OGI-147]
- Canadian Institutes of Health Research
- Ontario Research Fund
- Genome Alberta
- Genome British Columbia
- BC Children's Hospital Foundation
- BC Children's Hospital Research Institute
- BC Provincial Health Services Authority
- Genome Quebec
- Children's Hospital of Eastern Ontario Foundation
- Wellcome Trust
- Lundbeck Foundation [R277-2018-802]
- National Human Genome Research Institute of the National Institutes of Health [U01HG009599]
- NIH National Institute of Neurological Disorders and Stroke
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung and Blood Institute [UM1 HG008900]
- MRC [MR/T007087/1] Funding Source: UKRI
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This study provides a comprehensive description of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) with intellectual disability and early-onset epilepsy as core symptoms, mostly presenting before the age of two. The findings suggest an overlap with other genes encoding components of the SNARE complex, advancing the concept of SNAREopathies as a group of neurodevelopmental disorders.
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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