Abstract
Synaptotagmin-1 (SYT1) plays a pivotal role in regulating presynaptic processes, including neurotransmitter release. SYT1 variants perturb synaptic vesicle endocytosis and exocytosis, resulting in a series of neurodevelopmental disorders defined as Baker-Gordon syndrome. Herein, we report the case of a newborn with dysmorphic facial appearance, severe hypotonia, poor feeding, gastroesophageal reflux, and an inability to eat and breathe, diagnosed with Baker–Gordon syndrome. A retrospective search was performed on a newborn with Baker-Gordon syndrome. Medical charts were reviewed, with focus on the clinical presentation, diagnostic process, and treatment outcomes. Whole-genome high-throughput DNA sequencing was performed to identify genetic variants. Whole-exome sequencing identified the likely pathogenic variant as SYT1 C.551 T > C(p.V184A). Sanger sequencing results indicated that this variant was a de novo mutation in a conservative site located in the C2A domain of the protein. The patient died at 57 days old because of severe feeding and breathing problems. Our findings of a novel lethal variant in the C2A domain of SYT1 in the youngest patient diagnosed infantile Baker-Gordon syndrome who presented with the most severe hypotonia reported to date expands the spectrum of SYT1- associated neurodevelopmental disorders.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
John A, Ng-Cordell E, Hanna N et al (2021) The neurodevelopmental spectrum of synaptic vesicle cycling disorders. J Neurochem 157(2):208–228
Bradberry MM, Courtney NA, Dominguez MJ et al (2020) Molecular basis for synaptotagmin-1 associated neurodevelopmental disorder. Neuron 107(1):52-64.e7
Baker K, Gordon SL, Grozeva D et al (2015) Identification of a human synaptotagmin-1 mutation that perturbs synaptic vesicle cycling. J Clin Invest 125(4):1670–1678
Baker K, Gordon SL, Melland H et al (2018) SYT1-associated neurodevelopmental disorder: a case series. Brain 141(9):2576–2591
Melland H, Bumbak F, Kolesnik-Tatlor A et al (2022) Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder. Genet Med 24(4):880–893
Cafiero C, Marangi G, Orteschi D et al (2015) Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome. Eur J Hum Genet 23(11):1499–1504
Bai J, Wang P, Chapman ER (2002) C2A activates a cryptic Ca(2+)-triggered membrane penetration activity within the C2B domain of synaptotagmin I. Proc Natl Acad Sci USA 99(3):1665–1670
Südhof TC (2013) Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron 80(3):675–690
Shin OH, Xu J, Rizo J et al (2009) Differential but convergent functions of Ca2+ binding to synaptotagmin-1 C2 domains mediate neurotransmitter release. Proc Natl Acad Sci USA 106(38):16469–16474
Lee J, Guan Z, Akbergenova Y et al (2013) Genetic analysis of synaptotagmin C2 domain specificity in regulating spontaneous and evoked neurotransmitter release. J Neurosci 33(1):187–200
Gruget C, Bello O, Coleman J et al (2020) Synaptotagmin-1 membrane binding is driven by the C2B domain and assisted cooperatively by the C2A domain. Sci Rep 10(1):18011
Acknowledgements
All authors thank the patient and her parents whose participation in this research made this study possible.
Funding
This study was partly supported by the Hospital level project fund of Xi’an Children’s Hospital (2021H05).
Author information
Authors and Affiliations
Contributions
Ms Huang and Dr Zhao had full access to all the data in the study and take responsibility for the integrity and accuracy of the data. Concept and design: Wendi Huang, Ying Yang, and Yujuan Zhao. Acquisition and analysis of data: Fengyu Che, Haibin Wu, and Ying Ma. Drafting of manuscript: Wendi Huang and Ying Yang. Critical revision of manuscript: Ying Yang and Yujuan Zhao. Obtained funding: Wendi Huang. Administrative, technical or material support: Ying Yang, Fengyu Che, Haibin Wu, and Ying Ma.
Corresponding author
Ethics declarations
Declarations
This manuscript has not been published or presented elsewhere in part or in entirety and is not under consideration by another journal.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Xi’an Children’s Hospital (No. 20230013), and written informed consent was obtained from each participant or their guardians.
Consent for publication
The parents of the patient provided consent for publication, and the study design was approved by the appropriate ethics review board.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Huang, W., Yang, Y., Che, F. et al. Lethal variant in the C2A domain may cause severe SYT1-associated neurodevelopmental disorder in the newborns. Neurogenetics 25, 27–31 (2024). https://doi.org/10.1007/s10048-023-00738-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10048-023-00738-4