c.1103T>C (p.Ile368Th) de novo Variant in Synaptotagmin 1 (SYT1) Gene is Pathogenic, Leading to an Ultra-Rare Neurodevelopmental Disorder: The Baker-Gordon Syndrome

Abstract

Baker-Gordon Syndrome (BAGOS) is a genetically determined 4 (NDD), represented by a phenotypic spectrum of moderate to severe intellectual disability, resulting from mutations in the synaptotagmin 1 (SYT1) gene. Its prevalence is estimated at 1:1,000,000 and the known gene variants have indicated complete penetrance with variable expressivity. SYT1 is a membrane trafficking protein in presynaptic vesicles, which exerts a complex influence on synaptic transmission, with fundamental roles in the release of neurotransmitters and facilitators of endocytosis, impacting both neurotransmission and neuron plasticity. The current case report describes the first Brazilian male patient diagnosed at 17-year-old, and the 39th reported case globally using whole-exome sequencing. A de novo heterozygous missense mutation at chr12q:79448958 (NM_005639.2; c.1103T>C; p.Ile368Thr) in the SYT1 was found and classified as a pathogenic variant. The proband’s clinical phenotype was compatible with BAGOS, involving behavioral changes such as irritability and severe intellectual disability. Knowledge about the mechanism of action and the extent of the genotypic and phenotypic presentations of the mutations in the SYT1 is still unfolding. Thus, we aimed to describe additional genotype–phenotype correlation for BAGOS, contributing to the expansion of the existing knowledge of such a heterogeneous ultra-rare syndrome, and, therefore, improve its diagnostic yield, case management, and therapeutic journey for future patients.

Graphical Abstract

Keywords:

• SYT1
• hypotonia
• congenital malformations
• NDD
• WES

Data Sharing Statement

All data relevant to the current study were included in this manuscript and in DECIPHER database. This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Pontifical Catholic University of Goiás under CAAE # 67838022.9.0000.0037. Written informed consent was obtained from the proband’s parents which included consent to publish.

Acknowledgments

The authors are grateful for the important and generous contributions of each family to DECIPHER. We also appreciate the support of the multidisciplinary teams involved in the care of our patient, from clinicians to laboratory scientists involved in ending his diagnostic journey and assisting him and his family through this challenging health experience. We are also in debt to DECIPHER and its community for allowing the inclusion of information regarding individual patients in this report. Finally, we are grateful to Mr. Sean Quail for proofreading the manuscript.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Dr Raffael Zatarin reports non-financial support from BioMarin Pharmaceutical, non-financial support from PTC therapeutics, non-financial support from Chiesi Pharmaceuticals, non-financial support from Sanofi, non-financial support from Novartis, outside the submitted work. The authors have no other relevant financial or non-financial interests to disclose.

Additional information

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) of Brazil. This work has also been supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) of Brazil as the corresponding author holds a fellowship 1D. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from [email protected]. DECIPHER is hosted by EMBL-EBI and funding for the DECIPHER project was provided by the Wellcome Trust [grant number WT223718/Z/21/Z].