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. 2025 Jun;27(6):101419.
doi: 10.1016/j.gim.2025.101419. Epub 2025 Mar 19.

Clinical signatures of SYNGAP1-related disorders through data integration

Jillian L McKee  1 , Jan H Magielski  2 , Julie Xian  2 , Stacey Cohen  3 , Jonathan Toib  4 , Alicia Harrison  3 , Chen Chen  5 , Dan Kim  5 , Aakash Rathod  5 , Elise Brimble  6 , Nasha Fitter  6 , J Michael Graglia  7 , Kathryn A Helde  7 , Sarah McKeown Ruggiero  3 , Michael J Boland  8 , Benjamin L Prosser  8 , Rob Sederman  9 , Ingo Helbig  10
Affiliations

Clinical signatures of SYNGAP1-related disorders through data integration

Jillian L McKee et al. Genet Med. 2025 Jun.

Abstract

Purpose: SYNGAP1 is a genetic neurodevelopmental disorder characterized by generalized epilepsy, autism, and intellectual disability. Despite a comparatively high prevalence, the longitudinal landscape remains relatively unexplored, and complete characterization is essential for clinical trial readiness.

Methods: We combined electronic medical record data (n = 158) with insurance claims data (n = 246) to evaluate longitudinal progression of symptoms.

Results: Phenotypes associated with SYNGAP1 included behavioral abnormalities (odds ratio [OR]: 12.35, 95% CI: 9.21-16.78), generalized-onset seizures (OR: 1.56, 95% CI: 1.20-2.02), autism (OR: 12.23, 95% CI: 9.29-16.24), and a developmental profile with prominent deficits in verbal skill acquisition. Several clinical features showed distinct age-related patterns, such as a more than 5-fold risk of autistic behavior emerging between 27 and 30 months. Generalized-onset seizures were significantly increased (OR: 4.05, 95% CI: 2.02-7.59) after 3 years of age and persisted over time. Valproic acid and clobazam were commonly used for epilepsy treatment, whereas risperidone, aripiprazole, and guanfacine were commonly used for behavior management. Valproate and lamotrigine were more effective at reducing seizure frequencies or maintaining seizure freedom than other antiseizure medications.

Conclusion: We delineated the seizure, developmental, and behavioral trajectories in SYNGAP1-related disorders, to improve diagnosis, prognosis, and clinical care, and facilitating clinical trial readiness.

Keywords: Developmental and epileptic encephalopathy; Electronic medical record; Human phenotype ontology; Neurogenetics; SYNGAP1.

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Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

References

    1. López-Rivera JA, Pérez-Palma E, Symonds J, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain. 2020;143(4):1099–1105. - PMC - PubMed
    1. Hamdan FF, Gauthier J, Spiegelman D, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. New England Journal of Medicine. 2009;360(6):599–605. - PMC - PubMed
    1. Agarwal M, Johnston MV, Stafstrom CE. SYNGAP1 mutations: Clinical, genetic, and pathophysiological features. International Journal of Developmental Neuroscience. 2019;78:65–76. - PubMed
    1. Holder JL Jr, Hamdan FF, Michaud JL. SYNGAP1-related intellectual disability. 2019; - PubMed
    1. Kilinc M, Creson T, Rojas C, et al. Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders. Molecular and Cellular Neuroscience. 2018;91:140–150. - PMC - PubMed

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