Abstract
Purpose: 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 880-893 |
| Number of pages | 14 |
| Journal | Genetics in Medicine |
| Volume | 24 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2022 |
Funding
We appreciate the important and generous contributions of each individual with a SYT1 variant, their families, and carers. We appreciate the roles of each clinician and laboratory scientist involved in the diagnostic pathway of each case. Furthermore, we appreciate the involvement of individuals in the comparison intellectual disability group and their families and carers. We acknowledge the NIHR UK Rare Genetic Disease Research Consortium for assistance with recruitment to the study. H.M. was supported by an Australian Government Research Training Program Scholarship . S.L.G. and H.M. were supported by Grant 2003710 from The National Health and Medical Research Council of Australia and a Florey Fellowship. The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government, Australia and, in particular, the funding provided from the Operational Infrastructure Support Grant . This project was supported by funding to K.B. from the UK Medical Research Council (G101400), the Baily Thomas Charitable Trust, and the Great Ormond Street Hospital Children’s Charity. F.B. and J.J.Z. were supported by the Indiana University Precision Health Initiate . Molecular dynamics simulations were supported, in part, by Lilly Endowment, Inc through its support for the Indiana University Pervasive Technology Institute. We thank Dr Trayder Thomas (University of Chicago) and Dr Billy Williams-Noonan (RMIT University) for assistance with molecular dynamics simulations. This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected] . Funding for the DECIPHER project was provided by the Wellcome Trust. Individuals who contributed to DECIPHER bear no responsibility for the interpretation of the data by the authors. We acknowledge the Deciphering Developmental Disorders (DDD) study for identification of variants reported in this paper. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). See Nature 2015; 519:223-8 or www.ddduk.org/access.html for full acknowledgment. We appreciate the important and generous contributions of each individual with a SYT1 variant, their families, and carers. We appreciate the roles of each clinician and laboratory scientist involved in the diagnostic pathway of each case. Furthermore, we appreciate the involvement of individuals in the comparison intellectual disability group and their families and carers. We acknowledge the NIHR UK Rare Genetic Disease Research Consortium for assistance with recruitment to the study. H.M. was supported by an Australian Government Research Training Program Scholarship. S.L.G. and H.M. were supported by Grant 2003710 from The National Health and Medical Research Council of Australia and a Florey Fellowship. The Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government, Australia and, in particular, the funding provided from the Operational Infrastructure Support Grant. This project was supported by funding to K.B. from the UK Medical Research Council (G101400), the Baily Thomas Charitable Trust, and the Great Ormond Street Hospital Children's Charity. F.B. and J.J.Z. were supported by the Indiana University Precision Health Initiate. Molecular dynamics simulations were supported, in part, by Lilly Endowment, Inc through its support for the Indiana University Pervasive Technology Institute. We thank Dr Trayder Thomas (University of Chicago) and Dr Billy Williams-Noonan (RMIT University) for assistance with molecular dynamics simulations. This study makes use of data generated by the DECIPHER community. A full list of centers that contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected]. Funding for the DECIPHER project was provided by the Wellcome Trust. Individuals who contributed to DECIPHER bear no responsibility for the interpretation of the data by the authors. We acknowledge the Deciphering Developmental Disorders (DDD) study for identification of variants reported in this paper. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). See Nature 2015; 519:223-8 or www.ddduk.org/access.html for full acknowledgment. Conceptualization: K.B. H.M. S.L.G.; Formal Analysis: F.B. K.B. A.K.-T. A.J.; Funding Acquisition: K.B. S.L.G.; Investigation: F.B. H.M. A.K.-T. K.B. E.N.-C. A.J.; Resources: J.J.Z. P.C. S.J. M.L. C.F. J.T. F.E. M.W. T.K. R.P. R.B. R.C. L.L. M.A. J.v.d.S. M.N. M.K.; Visualization: H.M. A.K.-T. F.B.; Writing-original draft: H.M. K.B. F.B.; Writing-review and editing: H.M. K.B. S.L.G. D.J.S. All other authors reviewed and approved this manuscript. This study was conducted within the ?Phenotypes in Intellectual Disability? project, which received approval from the Cambridge Central Research Ethics Committee (REC ref: IRAS 83633). Written informed consent was provided by each diagnosed individual's parent or consultee prior to information sharing by referring clinicians and questionnaire completion by the parents or carers.
Keywords
- Intellectual disability
- Neurotransmission
- Synapse
- Synaptic vesicle
- Synaptotagmin
ASJC Scopus subject areas
- Genetics(clinical)