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.”
| Original language | English |
|---|---|
| Pages (from-to) | 653-660 |
| Number of pages | 8 |
| Journal | Genetics in Medicine |
| Volume | 23 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2021 |
Bibliographical note
Publisher Copyright:© 2020, American College of Medical Genetics and Genomics.
Funding
We thank the patients and their families for their participation and support of this study. We especially thank Elizabeth Dellureficio for her continuous efforts to bring affected families together. Work on individual 5 was supported in part by grants from SFARI and the JPB Foundation. We thank the clinicians involved with the care of these patients including Stephen Nirmal, Alasdair Parker, and Manali Chitre, UK. A.M., K.B., and M.A.K. are funded by the National Institute for Health Research (NIHR) GOSH BRC. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Individual 7 was enrolled in the NIHR BioResource research study, supported by the Cambridge Biomedical Research Centre and the NIHR for the NIHR BioResource (grant number RG65966). Individual 17 was ascertained in the Duke Genome Sequencing Clinic. Funding for the Duke Genome Sequencing Clinic which is supported by the Duke University Health System. Individual V6 was enrolled in Care4Rare Canada Consortium, funded by 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, and Children’s Hospital of Eastern Ontario Foundation. This study makes use of data generated by the DECIPHER Consortium. A full list of centers who contributed to the generation of the data is available from https://decipher.sanger.ac.uk/ and via email from [email protected]. Funding for the project was provided by the Wellcome Trust. R.S.M. was supported by a grant from the Lundbeck Foundation (R277-2018-802). Funding for the Duke Genome Sequencing Clinic was provided by Duke University Health System. Research reported in this publication was supported by the National Human Genome Research Institute of the National Institutes of Health under award number U01HG009599. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Katherine R. Chao for her help with the exome data analysis. The work in C.G. Bönnemann’s laboratory is supported by intramural funds from the NIH National Institute of Neurological Disorders and Stroke. Sequencing and analysis were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 to Daniel MacArthur and Heidi Rehm.
| Funders | Funder number |
|---|---|
| Duke University Health System | |
| Harvard Center for Mendelian Genomics | |
| National Institutes of Health (NIH) | |
| National Heart, Lung, and Blood Institute (NHLBI) | UM1 HG008900 |
| National Human Genome Research Institute | U01HG009599 |
| National Eye Institute/National Institutes of Health | |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | ZIANS003129 |
| JPB Foundation | |
| Genome Canada | |
| Wellcome Trust | |
| Ontario Research Foundation | |
| Broad Institute | |
| Simons Foundation Autism Research Initiative | |
| Children's Hospital of Eastern Ontario Foundation | |
| Canadian Institutes of Health Research | |
| Ontario Genomics Institute | OGI-147 |
| National Institute for Health Research Health Protection Research Unit | |
| Lundbeckfonden | R277-2018-802 |
| Genome Alberta | |
| UCLH Biomedical Research Centre | RG65966 |
ASJC Scopus subject areas
- Genetics(clinical)