SYT1-associated neurodevelopmental disorder: a case series.

Brain
Authors
Keywords
Abstract

Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.

Year of Publication
2018
Journal
Brain
Volume
141
Issue
9
Pages
2576-2591
Date Published
2018 09 01
ISSN
1460-2156
DOI
10.1093/brain/awy209
PubMed ID
30107533
PubMed Central ID
PMC6113648
Links
Grant list
UM1 HG008900 / HG / NHGRI NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States
R01 HG009141 / HG / NHGRI NIH HHS / United States
UM1 HG007301 / HG / NHGRI NIH HHS / United States
MC_UU_00005/16 / MRC_ / Medical Research Council / United Kingdom
WT_ / Wellcome Trust / United Kingdom
RP-2016-07-019 / DH_ / Department of Health / United Kingdom
SUAG/034/RG91365 / MRC_ / Medical Research Council / United Kingdom