SYNGAP1 – three things to know in 2023

Postsynaptic. SYNGAP1-related disorders are among the most common genetic developmental and epileptic encephalopathies with a unique clinical presentation. However, since the initial gene discovery in 2009, the clinical spectrum has expanded significantly to include a wider range of epilepsies and seizure types. Additionally, the SYNGAP1 community has grown to encompass hundreds of individuals reported in the literature or organized in advocacy organizations. Accordingly, we wanted to use the opportunity to update our SYNGAP1 page. Here are three things to know about SYNGAP1 in 2023.

Figure 1. Spectrum of disease-causing variants in SYNGAP1. (A) Selection of variants reported in the literature since 2015, updated since our prior blog post. (B) Types of variants reported in the SYNGAP1 gene, demonstrating the wide range of genetic changes identified through diagnostic testing.

1 – SYNGAP1 and MAE. SYNGAP1  is one of the few monogenic causes of generalized epilepsy, including myoclonic astatic epilepsy (MAE), also known as Doose Syndrome. MAE has previously been an understudied, rare childhood epilepsy with a classically unremarkable work-up in affected individuals. Additionally, not all individuals with MAE have developmental differences. Although it is presumably a genetically heterogeneous condition, SYNGAP1 has been identified as one of only three monogenic causes, along with NEXMIF and SLC6A1. Identifying a triad of genes associated with MAE supports the clinical importance of genetic testing for affected individuals and helps characterize epilepsy features in individuals affected by SYNGAP1.

2 –Genotype-phenotype correlations. Despite SYNGAP1 captivating the interest of numerous researchers since its discovery in 2009, genotype-phenotype correlations remain elusive. To date, there are no known correlations, although there are research studies in place attempting to answer this question through natural history studies and disease concept models. In a study by Vlaskamp and collaborators, a milder phenotype of SYNGAP1-related DEE was more frequently associated with pathogenic or likely pathogenic variants in exons 1 to 4 compared to exons 5 to 19. However, variable phenotypes were still observed in individuals with the same variant, including siblings. Preliminary data by Jillian McKee from our group presented at the 2022 AES meeting suggest there may be unique phenotypic characteristics of protein-truncating variants compared to missense variants within SYNGAP1, such as increased prevalence of atypical absence seizures, ataxia, and tremor. As we further characterize the full spectrum of SYNGAP1-related disorders, emerging knowledge on how specific genotypes link to clinical presentations will be critical for clinical management and future trials.

3 – A strong SYNGAP1 community. Along with a progressive research scene, SYNGAP1 has a very active community of supporting families and providing resources through two major advocacy foundations. The SyngGAP Research Fund is a non-profit organization for SYNGAP1 families and researchers. Along with providing various educational resources online, the foundation hosts an annual conference and has partnered with healthcare institutions spearheading SYNGAP1 research advancements. The SYNGAP1 Foundation is a prominent nonprofit patient advocacy organization. This foundation focuses on educating and advocating for families through advocacy initiatives, educational programs, and research collaborations. Both of these family foundations are interested in furthering natural history studies describing the longitudinal prognosis to better serve the SYNGAP1 community.

Natalie is a licensed certified genetic counselor at the Children’s Hospital of Philadelphia.