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

Abstract

Purpose This 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. Methods Individuals harboring heterozygous missense or truncating variants in SNAP25 were assembled through a collaboration with international colleagues, matchmaking platforms and literature review. For each individual, detailed phenotyping, classification and structural modeling of the identified variant was performed. Results The cohort comprises 20 individuals with (likely) pathogenic 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. Conclusion We provide a first comprehensive description of SNAP25-DEE with intellectual disability and early onset epilepsy mostly occurring before the age of two years. Other recurrent phenotypes such as movement disorders, cortical visual impairment and brain atrophy show an overlap to other genes encoding components of the SNARE complex such as STXBP1 or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed SNAREopathies.

Disorders of synaptic vesicle fusion machinery

“…Additionally, the number of docked synaptic vesicles observed by electron microscopy was dramatically reduced (Imig et al, 2014). , Shen et al, 2014, Hamdan et al, 2017, Fukuda et al, 2018, Klöckner et al 2020) Cerebral and cerebellar atrophy. (Boehme et al, 1971;Burgoyne & Morgan, 2015;Cadieux-Dion et al, 2013;Noskova et al, 2011;Velinov et al, 2012) α-synuclein All variants are de novo heterozygous mutations, including four missense mutations (A67P, S75P, F77S, E78A) and two single amino acid deletions (V43del, I45del) (Salpietro et al, 2019;Sunaga et al, 2020) (Figure 1).…”

“…All identified mutations occur in the SNARE motifs and are predicted to destabilise the SNARE complex or disrupt interactions with key binding partners including synaptotagmin‐1 and αSNAP (Klöckner et al, 2020; Zhou et al., 2015), but detailed functional studies are largely lacking. Of the published mutations, only I67N and D166Y have experimental evidence of pathogenicity.…”

“…Seven published heterozygous mutations in SNAP-25 have been found in individuals with neurodevelopmental delay and epilepsy (Heyne et al, 2018). A further 10 variants have very recently been identified in a comprehensive phenotypic characterisation of SNAP-25 developmental and epileptic encephalopathy (DEE; preprint (Klöckner et al, 2020)). Mild to profound intellectual disability was observed in all cases and many presented with other neurological comorbidities.…”

Molecule-to-Circuit Disease Mechanisms of a Synaptic SNAREopathy

“…Acute inactivation through botulinum neurotoxins (Figure 1) leads to life-threatening paralysis (Schiavo et al, 2000). Its genetic mutations cause developmental and epileptic encephalopathy (DEE) of infancy and childhood, with neurological symptoms varying with the nature of the mutations (Klo ¨ckner et al, 2020).…”

“…These residues are of paramount importance for SNARE function, and mutations in these sites across different SNARE complexes and across evolution are often detrimental (Praschberger et al, 2017). Intriguingly, a large proportion of the SNAP25-DEE mutations affect either N-or C-terminal layer residues (Alten et al, 2020;Klo ¨ckner et al, 2020), implying altered SNARE motif zippering. Another set of mutations affect residues at the interface between SNAP25 and the C2B domain of synaptotagmin 1-the principal calcium sensor to enable electrical-to-chemical signal conversion in the process of synaptic vesicle fusion and neurotransmitter release.…”