Objectives We describe the clinical manifestations and developmental abilities of individuals with SYT1-associated neurodevelopmental disorder (Baker-Gordon syndrome) from infancy to adulthood. We further describe the neuroradiological and electrophysiological characteristics of the condition at different ages, and explore the associations between these characteristics and clinical symptoms.

Methods Participants were recruited to the UK-based Brain and Behavior in Neurodevelopmental Disorders of Genetic Origin project. Caregivers completed a medical history questionnaire and a battery of standardized neurodevelopmental measures. MRI and EEG records were obtained with consent from treating clinicians. Age-related clinical manifestations and neuroimaging records were systematically analyzed. Accuracy testing was used to explore brain-symptom associations.

Results This study describes 39 individuals with 29 distinct de novo SYT1 missense variants, including 11 novel variants. Qualitative age-related clinical trends included the resolution of hypotonia and worsening of movement disorders, sleep difficulties, and self-injurious behaviors. Social-communicative impairments were prominent, with evidence of progression with age. MRI abnormalities were identified in 48% of individuals, while EEG abnormalities were present in 92%. Epileptiform activity frequently co-occurred with movement disorders, while irregular sleep EEG coincided with sleep difficulties and respiratory problems.

Interpretation This study characterizes the broad spectrum and age-related progression of clinical symptoms and brain-related findings in individuals with SYT1-associated neurodevelopmental disorder. Further research is needed to understand factors contributing to within-individual change, and to develop targeted interventions aimed at improving outcomes and quality of life for affected individuals and their families.

The authors have declared no competing interest.

This work was funded by the Medical Research Council (MC_UU_00030/3), Great Ormond Street Hospital Charity, Cambridge NIHR Biomedical Research Centre, and Gates Cambridge.

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Cambridge Central Research Ethics Committee gave ethical approval for this work (IRAS 83633, REC ref: 11/0330/EE).

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