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Brain. 2018 Sep 1;141(9):2576-2591. doi: 10.1093/brain/awy209.

SYT1-associated neurodevelopmental disorder: a case series.

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Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Wellcome Trust / MRC Building, Hills Road, Cambridge, UK.
MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge, UK.
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia.
Department of Biochemistry and Molecular Biology, University of Melbourne, 30 Royal Parade, Parkville, VIC, Australia.
Department of Clinical Biochemistry, Cambridge Institute for Medical Research, Hills Road, Cambridge, UK.
Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, UK.
Ambry Genetics, 15 Argonaut, Aliso Viejo, CA, USA.
Department of Clinical Genetics, Queen Rania Al-Abdullah Children Hospital, King Hussein Medical Centre, Royal Medical Services, Amman, Jordan.
Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
University of Missouri Health Care, Columbia, MO, USA.
Department of Clinical Genetics, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.
Institute of Genomic Medicine, Catholic University, A. Gemelli Foundation, Roma, Italy.
Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Dr. von Hauner's Children's Hospital, University of Munich, Munich, Germany.
Institute of Human Genetics, Technische Universität München, Munich, Germany.
Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Flemington Road, Parkville VIC, Australia.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Human Genome Sequencing Center, Baylor College of Medicine, Texas, USA.
Maine Medical Partners Pediatric Specialty Care, Congress St, Portland ME, USA.
HudsonAlpha Institute for Biotechnology, 601 Genome Way NW, Huntsville, AL, USA.
Centre for Discovery Brain Sciences, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh, UK.


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.

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