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

Abstract

ABSTRACTPurposeThis study aims to provide the first comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25- DEE) by reviewing newly identified and previously reported individuals.MethodsIndividuals harboring heterozygous missense or truncating 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 was performed.ResultsThe cohort comprises 20 individuals with (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, cortical 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.ConclusionWe provide a first 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”.