In this review, we describe and discuss neurodevelopmental phenotypes arising from rare, high penetrance genomic variants which directly influence synaptic vesicle cycling (SVC disorders). Pathogenic variants in each SVC disorder gene lead to disturbance of at least one SVC sub-process, namely vesicle trafficking (for example KIF1A and GDI1), clustering (for example TRIO, NRXN1 and SYN1), docking and priming (for example STXBP1), fusion (for example SYT1 and PRRT2) or re-uptake (for example DNM1, AP1S2 and TBC1D24). We observe that SVC disorders share a common set of neurological symptoms (movement disorders, epilepsies), cognitive impairments (developmental delay, intellectual disabilities, cerebral visual impairment) and mental health difficulties (autism, ADHD, psychiatric symptoms). On the other hand, there is notable phenotypic variation between and within disorders, which may reflect selective disruption to SVC sub-processes, spatiotemporal and cell-specific gene expression profiles, mutation-specific effects, or modifying factors. Understanding the common cellular and systems mechanisms underlying neurodevelopmental phenotypes in SVC disorders, and the factors responsible for variation in clinical presentations and outcomes, may translate to personalised clinical management and improved quality of life for patients and families.This article is protected by copyright. All rights reserved.
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Abinayah John,Elise Ng-Cordell,Nancy Hanna,Diandra Brkic,Kate Baker