Variants of TSC1 are associated with developmental and epileptic encephalopathy and focal epilepsy without tuberous sclerosis : For the China Epilepsy Gene 1.0 Project.

Background: The TSC1 gene encodes a growth inhibitory protein hamartin, which plays a crucial role in negative regulation of the activity of mTORC1 (mechanistic target of rapamycin complex 1). TSC1 has been associated with tuberous sclerosis complex (TSC). This study aims to investigate the association between TSC1 variants and common epilepsy.

Methods: Trio-based whole-exome sequencing was performed in epilepsy patients without acquired etiologies from the China Epilepsy Gene 1.0 Project platform. The pathogenicity of the variants was evaluated according to the American College of Medical Genetics and Genomic (ACMG) guidelines.

Results: Two TSC1 de novo variants, including c.1498 C > T/p.Arg500* and c.2356 C > T/p.Arg786*, were identified in two patients with developmental and epileptic encephalopathy (DEE). The patients exhibited frequent seizures and neurodevelopmental delay. Additionally, we identified two heterozygous TSC1 variants that affected four individuals with focal epilepsy from two unrelated families. The four probands did not present any typical symptom of TSC and had normal brain MRI findings. The four variants were absent in the Genome Aggregation Database (gnomAD) and were predicted to be damaging with a in silico prediction tool. Based on the ACMG guidelines, the four variants were evaluated to be "pathogenic" or "likely pathogenic". Of the patients in the China Epilepsy Gene 1.0 Project, 22 patients carried TSC1 variants and were diagnosed with TSC. The ratio of patients carrying TSC1 variants with or without TSC is about 5:1.

Conclusions: TSC1 is potentially associated with common epilepsy without tuberous sclerosis.