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dc.contributor.authorMelland, Holly
dc.contributor.authorBumbak, Fabian
dc.contributor.authorKolesnik-Taylor, Anna
dc.contributor.authorNg-Cordell, Elise
dc.contributor.authorJohn, Abinayah
dc.contributor.authorConstantinou, Panayiotis
dc.contributor.authorJoss, Shelagh
dc.contributor.authorLarsen, Martin
dc.contributor.authorFagerberg, Christina
dc.contributor.authorLaulund, Lone Walentin
dc.contributor.authorThies, Jenny
dc.contributor.authorEmslie, Frances
dc.contributor.authorWillemsen, Marjolein
dc.contributor.authorKleefstra, Tjitske
dc.contributor.authorPfundt, Rolf
dc.contributor.authorBarrick, Rebekah
dc.contributor.authorChang, Richard
dc.contributor.authorLoong, Lucy
dc.contributor.authorAlfadhel, Majid
dc.contributor.authorvan der Smagt, Jasper
dc.contributor.authorNizon, Mathilde
dc.contributor.authorKurian, Manju A
dc.contributor.authorScott, Daniel J
dc.contributor.authorZiarek, Joshua J
dc.contributor.authorGordon, Sarah L
dc.contributor.authorBaker, Kate
dc.date.accessioned2022-06-21T23:30:58Z
dc.date.available2022-06-21T23:30:58Z
dc.date.issued2022-04
dc.identifier.issn1098-3600
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338278
dc.description.abstractPURPOSE: Synaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioral disturbances, and electroencephalogram abnormalities. In this study, we expand the genotypes and phenotypes and identify discriminating features of this disorder. METHODS: We describe 22 individuals with 15 de novo missense SYT1 variants. The evidence for pathogenicity is discussed, including the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, known structure-function relationships, and molecular dynamics simulations. Quantitative behavioral data for 14 cases were compared with other monogenic neurodevelopmental disorders. RESULTS: Four variants were located in the C2A domain with the remainder in the C2B domain. We classified 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes included delayed developmental milestones, abnormal eye physiology, movement disorders, and sleep disturbances. Discriminating behavioral characteristics were severity of motor and communication impairment, presence of motor stereotypies, and mood instability. CONCLUSION: Neurodevelopmental disorder-associated SYT1 variants extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severities than initially reported. This study guides the diagnosis and molecular understanding of this rare neurodevelopmental disorder and highlights a key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function.
dc.format.mediumPrint-Electronic
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectIntellectual disability
dc.subjectNeurotransmission
dc.subjectSynapse
dc.subjectSynaptic vesicle
dc.subjectSynaptotagmin
dc.subjectCalcium
dc.subjectGenotype
dc.subjectHumans
dc.subjectIntellectual Disability
dc.subjectMovement Disorders
dc.subjectNeurodevelopmental Disorders
dc.subjectPhenotype
dc.subjectSynaptotagmin I
dc.titleExpanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder.
dc.typeArticle
dc.publisher.departmentMrc Cognition And Brain Sciences Unit
dc.date.updated2022-06-21T08:02:07Z
prism.endingPage893
prism.issueIdentifier4
prism.publicationDate2022
prism.publicationNameGenet Med
prism.startingPage880
prism.volume24
dc.identifier.doi10.17863/CAM.85686
dcterms.dateAccepted2021-12-03
rioxxterms.versionofrecord10.1016/j.gim.2021.12.002
rioxxterms.versionVoR
dc.contributor.orcidBaker, Kate [0000-0003-2986-0584]
dc.identifier.eissn1530-0366
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_00005/16)
cam.issuedOnline2022-01-29
cam.depositDate2022-06-21
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International