SYT1 – Baker-Gordon syndrome

Synaptotagmin-1 (SYT1) is a presynaptic Ca²⁺ sensor that triggers fast synchronous neurotransmitter release and regulates vesicle endocytosis. Heterozygous de novo missense variants in SYT1 disrupt these processes, leading to infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome (Baker-Gordon syndrome) (SYT1; Baker-Gordon syndrome).

Clinical genetic studies have identified at least 39 unrelated probands with de novo SYT1 missense variants ([PMID:30107533]; [PMID:35101335]; [PMID:38283597]) presenting with hypotonia, oculomotor abnormalities, hyperkinetic movements, developmental delay, feeding difficulties, and gastroesophageal reflux. No familial inheritance beyond de novo occurrence has been reported, and variants are absent from large population databases.

Pathogenic variants cluster in the C2 domains of SYT1, most frequently in C2B. A recurrent example is c.1103T>C (p.Ile368Thr) confirmed as de novo in multiple cases ([PMID:30107533]). This and other variants affect conserved Ca²⁺-binding loops or interdomain interfaces critical for membrane and SNARE interactions.

Functional assays in primary neuronal cultures and molecular dynamics simulations demonstrate that SYT1 missense variants act in a dominant-negative manner, impairing synchronous exocytosis, enhancing asynchronous and spontaneous release, and disrupting Ca²⁺-dependent conformational dynamics ([PMID:30107533]; [PMID:32362337]; [PMID:25992729]). Rescue experiments with pharmacologic modulators further confirm variant-specific dysfunction ([PMID:32362337]).

No conflicting genetic or functional data have been reported. The consistency of de novo segregation and concordant experimental findings across multiple studies establishes a robust gene–disease relationship.

Integration of genetic and experimental evidence supports a Strong clinical validity classification. SYT1 sequencing should be incorporated into diagnostic panels for early-onset hypotonia with movement disorders, enabling accurate diagnosis, genetic counseling, and consideration of targeted therapies.

References

• Brain • 2018 • SYT1-associated neurodevelopmental disorder: a case series PMID:30107533
• Genetics in medicine • 2022 • Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder PMID:35101335
• Neurogenetics • 2024 • Lethal variant in the C2A domain may cause severe SYT1-associated neurodevelopmental disorder in the newborns PMID:37930470

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