Abstract
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. KIF1A and GDI1), clustering (e.g. TRIO, NRXN1 and SYN1), docking and priming (e.g. STXBP1), fusion (e.g. SYT1 and PRRT2) or re-uptake (e.g. 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 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.
Highlights
Neurodevelopmental disorders encompass diverse, dynamic and interactive childhood-onset symptoms, which can include sensory deficits, motor impairments, epilepsies, intellectual disabilities and mental health difficulties
Our literature review indicated that developmental delay (DD)/Intellectual disability (ID) is reported in all synaptic vesicle cycling (SVC) disorders, but varies in prevalence from being universally reported in around two thirds of disorders, to only sometimes or rarely reported in the remainder
It is noteworthy that mental health diagnoses appear to be especially common in SVC disorders associated with a milder range of ID
Summary
Neurodevelopmental disorders encompass diverse, dynamic and interactive childhood-onset symptoms, which can include sensory deficits, motor impairments, epilepsies, intellectual disabilities and mental health difficulties. Genomic analysis can diagnose a specific cause in 60% of severely affected children (Gilissen et al, 2014), and the catalogue of genetic diagnoses associated with neurodevelopmental disorders has rapidly expanded to more than 1,500 confirmed genes (https://www.ebi.ac.uk/gene phenotype). This step-change in aetiological diagnosis yields new opportunities to understand the multi-level mechanisms contributing to each individual's difficulties and, potentially, to treat their underlying brain dysfunction rather than (or in addition to) their onthe-surface symptoms. Considering both sources of information, we discuss reasons for phenotypic similarity and variation within the SVC disorders network
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
