Authors :
Presenting Author: Jillian McKee, MD, PhD – Children's Hospital of Philadelphia & University of Pennsylvania
Alicia Harrison, MS, LCGC – CHOP
Jan Magielski, BA – CHOP
Jonathan Toib, MD – CHOP
Sarah Tefft, MSN, RN, CRNP – Children's Hospital of Philadelphia
Sarah Ruggiero, MS, CGC – Children's Hospital of Philadelphia
JoeyLynn Coyne, RT – Children's Hospital of Philadelphia
Samuel Pierce, PT, PhD – Children's Hospital of Philadelphia
Kristin Cunningham, MS, OTR/L – Children's Hospital of Philadelphia
Michael Kaufman, MS – Children's Hospital of Philadelphia
Carlyn Glatts, MD – Children's Hospital of Philadelphia
Hillary Kruger, MD – CHOP
Macie McCarthy, BA – CHOP
Johanna Mercurio, BS, BSFCS – CHOP
Viveknarayanan Padmanabhan, MS – CHOP
Virginie McNamar, MA – Syngap Research Fund
J Michael Graglia, BS – Syngap Research Fund
Kathryn Helde, PhD – SynGAP Research Fund
Megan Abbott, MD – University of Colorado
Katherine Xiong, MD – Stanford
Juliet Knowles, MD/PhD – Stanford University
Benjamin Prosser, PhD – Penn
Michael Boland, PhD – Penn
Ingo Helbig, MD – Children's Hospital of Philadelphia
Rationale:
SYNGAP1-related disorder is a common monogenic cause of generalized epilepsy, autism, and intellectual disability, with targeted therapeutics currently under development. Given the multiple isoforms of the SYNGAP1 gene and the broad clinical spectrum of the disease, it has been hypothesized that milder clinical presentations may result from variants occurring in the first four exons. Often referred to as “early” variants in the community, these changes occur prior to the initiation site of certain isoforms, leaving transcription of these alternative versions of SYNGAP1 intact. Here, we test this hypothesis by comparing the clinical spectrum of individuals with “early” versus “late” variants using standardized developmental assessments, as understanding the clinical relevance of the different SYNGAP1 isoforms and genotype-phenotype correlations is critical for the design of disease-modifying therapies and subsequent clinical trials.
Methods:
We report data from an IRB-approved, single-site natural history study as part of the SYNGAP1 ProMMiS study. Inclusion criteria include a molecular diagnosis of SYNGAP1-related disorder, and individuals are excluded if they have an additional genetic or neurologic diagnosis contributing to their clinical presentation. Monthly seizure histories, including seizure types and frequencies, are reconstructed from medical records. Study visits occur every 6 months and include standardized clinical histories, neurological examinations, caregiver-reported outcomes, clinical scales, and standardized assessments, as appropriate given the age and developmental level of the participant. To assess the developmental differences in those with early versus late variants, we employ generalized linear models for all continuous, non-normally distributed outcomes and proportional-odds cumulative link models for the ordinal scales, in each case including age as a covariate.
Results:
108 individuals with SYNGAP1 were evaluated. Ages at initial assessment ranged from 1.6 to 67.5 years (median 6.3 years). 12% (N=13/108) had variants in the first four exons, with 8 located in exons 1-3a affecting isoform A, and 5 located in exon 3b and affecting only isoform B. When analyzed jointly, individuals with these early variant classes affecting only a subset of the major SYNGAP1 isoforms had milder clinical presentations when assessed via standardized clinical scales (Table 1, group p-values). These effects were consistent and strong, even after accounting for age-related differences, across scales assessing gross motor function, fine motor function and coordination, expressive and receptive communication, cognition, and symptoms of autism.
Conclusions:
After controlling for age, individuals harboring early SYNGAP1 variants affecting the first four exons exhibited significantly less severe scores on a wide range of developmental assessments. These results may have implications for patient stratification in upcoming clinical trials and strategies for isoform-targeted gene replacement therapies.
Funding:
The Center for Epilepsy and Neurodevelopmental Disorders, NINDS, AES, PERF, SynGAP Research Fund, AAN, EF, & ABF.