Genetic Study Reveals Inheritance Patterns in SYNGAP1 Disorders

Researchers at the Children's Hospital of Philadelphia (CHOP) have unveiled significant findings regarding SYNGAP1-related disorders, which are characterized by developmental delays and a high incidence of epilepsy. Their study, published in the journal *Epilepsia* on June 19, 2025, indicates that, although most cases arise from spontaneous genetic mutations, certain variants responsible for these disorders can be inherited from parents. This breakthrough has profound implications for genetic counseling, family planning, and the interpretation of genetic variants in clinical settings.

SYNGAP1-related disorders are caused by mutations in the SYNGAP1 gene, with symptoms typically manifesting as early childhood epilepsy combined with varying degrees of cognitive impairment. The research team, comprising members from the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP, identified instances where the genetic variants were shared among family members, suggesting a hereditary component in some cases. According to Alicia Harrison, a genetic counselor and the study's first author, "While inherited variants are not the norm for SYNGAP1-related disorders, understanding these rare cases will help us provide better counseling to parents who wish to have another child following a SYNGAP1 diagnosis."

The study analyzed eight individuals from three families, revealing that two families had inherited protein-truncating variants from a parent exhibiting symptoms of SYNGAP1-related disorders. The third family presented a mosaic parent, who carried the variant in a minor percentage of cells and showed no symptoms. Additionally, the research identified two families with missense variants, which could alter the function of the resulting protein, although their clinical significance remains uncertain.

Dr. Jillian McKee, a senior author and epileptologist specializing in neurogenetic disorders at CHOP, emphasized the importance of recognizing these familial variants, stating, "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."

The findings contribute to the ongoing SYNGAP1 ProMMiS natural history study, undertaken by CHOP and Penn Medicine, aimed at gathering extensive data on individuals with SYNGAP1-related disorders. This initiative seeks to track symptom progression and establish a foundation for future clinical trials. As research advances, accurate classification of genetic variants will become increasingly crucial in developing targeted therapies for patients.

The ongoing work at CHOP illustrates a progressive understanding of the complexities surrounding SYNGAP1-related disorders, particularly the role of inheritance in their manifestation. This knowledge not only aids in clinical care but also enhances awareness around the genetic implications for families affected by these disorders, marking a pivotal step in the field of genetic counseling and neurodevelopmental disorder research.