The neurodevelopmental spectrum of synaptic vesicle cycling disorders

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 subprocess, namely vesicle trafficking (e.g.KIF1AandGDI1), clustering (e.g.TRIO,NRXN1andSYN1), docking and priming (e.g.STXBP1), fusion (e.g.SYT1andPRRT2) or re-uptake (e.g.DNM1, AP1S2andTBC1D24). 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 subprocesses, 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 personalized clinical management and improved quality of life for patients and families.

Automated summary

This review examines the neurodevelopmental phenotypes resulting from rare genomic variants influencing synaptic vesicle cycling (SVC disorders), highlighting common neurological symptoms, cognitive impairments, and mental health difficulties shared by individuals with these disorders. There is significant phenotypic variation both between and within disorders, likely due to selective disruption to specific SVC subprocesses, mutation-specific effects, or modifying factors. Understanding the underlying mechanisms and factors responsible for this phenotypic variation may lead to personalized clinical management and improved quality of life for patients and families.