Researchers at the Children’s Hospital of Philadelphia (CHOP) have identified rare instances where SYNGAP1-related disorders, typically characterized by developmental delays and often associated with epilepsy, are caused by inherited genetic variants. This discovery could impact family planning and clinical care for affected families. The findings were published in the journal Epilepsia.
SYNGAP1-related disorders arise from variants in the SYNGAP1 gene. Most individuals with these disorders experience epilepsy starting in early childhood, alongside varying degrees of developmental delay and cognitive impairment. Behavioral differences, including autism spectrum disorder, may also be present.
While most cases are due to de novo genetic variants—spontaneous mutations not inherited from parents—the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP found some rare familial cases. “We realized that in some instances, people with SYNGAP1-related disorders went on to have children and were only diagnosed when their child was diagnosed,” said Alicia Harrison, a genetic counselor with ENGIN at CHOP. She noted that understanding these rare inherited cases will improve counseling for parents considering having more children after a SYNGAP1 diagnosis.
The study examined eight individuals across three families with inherited protein-truncating variants in the SYNGAP1 gene. In two families, the variant came from a heterozygous parent who had symptoms themselves; in the third family, it was inherited from a mosaic parent without symptoms.
Additionally, two families had missense variants of uncertain significance—variants causing amino acid substitutions affecting protein function—but further research is needed to understand their clinical impact.
Participants were identified through the SYNGAP1 ProMMiS natural history study conducted by CHOP’s Center for Epilepsy and Neurodevelopmental Disorders (ENDD) and Penn Medicine. This ongoing research aims to recruit as many individuals as possible to track symptom progression over time and prepare for future clinical trials.
“In conducting this study, we are meeting a large number of families with SYNGAP1,” said Jillian McKee, MD, PhD, an ENGIN epileptologist specializing in neurogenetic disorders at CHOP. “The familial variants we identified may be rare, but these ‘edge cases’ can provide valuable insight into the spectrum of symptoms and their genetic causes.”
This study received support from various organizations including ENDD, National Institute for Neurological Disorders and Stroke grants R01 NS127830-01A1, R01 NS131512-01 and K02 NS112600, American Epilepsy Society, Pediatric Epilepsy Research Foundations, SynGAP Research Fund through a Research Training Fellowship for Clinicians, American Academy of Neurology, Epilepsy Foundation and American Brain Foundation through the Susan Spencer Award.
Harrison et al., “Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy.” Epilepsia. Online May 23, 2025. DOI: 10.1111/epi.18469.
