Authors :
Presenting Author: Jillian McKee, MD, PhD – Children's Hospital of Philadelphia
Julie Xian, BS – Children's Hospital of Philadelphia; Chen Chen, BS, MA – Ambit, Inc.; Aakash Rathod, MS – Ambit, Inc.; Dan Kim, PhD – Ambit, Inc.; Stacey Cohen, MS, LCGC – Children's Hospital of Philadelphia; Jonathan Toib, BS – Children's Hospital of Philadelphia; Elise Brimble, MS, CGC – Ciitizen, Invitae; Nasha Fitter, BS, MBA – Ciitizen, Invitae; Rob Sederman, BS, MBA – Ambit, Inc.; Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale:
Disease causing variants in
SYNGAP1 are among the most common etiologies for non-syndromic intellectual disability with generalized epilepsy. However, in contrast to other genetic epilepsies such as Dravet Syndrome,
SYNGAP1-related disorders have received relatively little attention with regards to characterization of disease-specific trajectories. While the clinical landscape of
SYNGAP1-related remains relatively unexplored, it is essential for clinical trial readiness.
Methods:
Here, we identified clinical signatures associated with
SYNGAP1-related disorders across large-scale healthcare resources, harmonizing data from a single center (Children’s Hospital of Philadelphia, N=30), medical aggregators (Ciitizen, N=150) and insurance claims (Ambit, N=246). We mapped clinical annotations onto the human phenotype ontology (HPO) across >2500 patient years and retrieved 3643 anti-seizure and behavioral medication prescriptions for
SYNGAP1 patients in addition to 451,365 prescriptions in a broader cohort with epilepsy.
Results:
Compared to a broader population of individuals with epilepsy, clinical characteristics including 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 abnormality of higher mental function (including intellectual disability, OR 6.38, 95% CI 4.89 – 8.37) were enriched in individuals with
SYNGAP1. Over eighty percent of individuals with
SYNGAP1-related disorders have epilepsy (frequency of 0.654 in claims data), with a median onset of 26 months (IQR 24 months – 36 months, representing a relatively later onset than compared to other genetic epilepsies. The most prominent seizure types were generalized (Frequency [f]=0.435), including atonic seizures (f=0.215), absence seizures (f=0.118), and myoclonic-atonic seizures (f=0.285). Longitudinal reconstruction of medications for epilepsy management and behavioral features, including sleep disturbance and attention-related concerns, demonstrated age-related treatment strategies in individuals with
SYNGAP1 with predominance of valproic acid (OR 2.26, 95% CI 1.29 – 3.70) and clobazam (OR 2.58, 95% CI 1.55 – 4.09) for epilepsy and risperidone (OR 5.43, 95% CI 3.47 – 8.18), aripiprazole (OR 3.52, 95% CI 2.05 – 5.69) and guanfacine (OR 2.97, 95% CI 1.76 – 4.75) for behavior, which contrasted from treatment strategies frequently used in the broader epilepsy population.
Conclusions:
In summary, we characterized the landscape of
SYNGAP1-related disorders across >2500 patient-years, leveraging data from healthcare resources with varying scopes of clinical documentation and identified clinical signatures specific to
SYNGAP1. Clear delineation of epilepsy and developmental trajectories will improve the prognosis and clinical care of individuals with
SYNGAP1-related disorders and facilitate clinical trial readiness for future precision medicine approaches.
Funding:
Children’s Hospital of Philadelphia; National Institute of Neurological Disorders and Stroke, The Hartwell Foundation, Ambit, Inc.