Authors :
First Author: Seungyeul Yoo, PhD – GeneDx
Presenting Author: Jun Yu, –
Yu Liu, PhD – Data Science – GeneDx; Eunjee Lee, PhD – Data Science – GeneDx; Quan Chen, PhD – Data Science – GeneDx; Stephen McGee, PhD – Production Bioinformatics – GeneDx; Li Wang, PhD – Data Science – GeneDx; Jun Zhu, PhD – Data Science – GeneDx
Rationale:
Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic condition affecting 1 in 6000 newborns in the US and is driven by variants in TSC1 or TSC21. The brain is the primarily affected tissue with related neurologic disorders including epilepsy, developmental delay, and autism1. These brain disorders can occur early in life and have a high impact on the quality of life of patients and families. Clinical manifestations of TSC are very heterogeneous. The severity and age of onset of epilepsy are correlated with intellectual disability and autism2.
Methods:
The molecular function of TSC1 and TSC2 and molecular pathways regulated by TSC1/TSC2 are well studied1. TSC1 and TSC2 form a complex that inhibits the mTOR pathway, in turn regulating many pathways essential for cell growth in all cells. To understand the molecular mechanisms of TSC heterogeneity, we integrated diverse omics data at bulk tissue and single cell level to identify key molecular regulations underlying disease heterogeneity.
Results:
The mTOR pathway is essential to cell growth regulation in all types of cells, but transcription regulations of TSC1/TSC2/mTOR and mTOR complex 1 (mTORC1) activity in the brain are unique. The age of epilepsy onset is a surrogate biomarker for the disease severity of TSC. To access whether TSC1/TSC2 variants are associated with early (age < 2 years old) vs. late (age ≥ 2 years old) onset of epilepsy, we compared TSC1/TSC2 variants of TSC patients in the GeneDx database and found no clear difference in variants associated with early vs. late onset of epilepsy (Fig. 1).
Next, we compared transcription profiles of brain tissues from TSC patients3 and identified a signature differentiating patients with early vs. late onset of epilepsy (Fig. 2A). The genes upregulated in the brains of TSC patients with early-onset epilepsy were enriched for genes in immune response (Fig. 2B). To test whether baseline immune pathway activity is different between TSC patients with early vs. late onset of epilepsy, we imputed the brain gene expression profile of each patient based on genotypes derived from whole exome sequencing data and then refined the brain gene expression profiles based on constructed brain molecular causal networks. Preliminary results suggest that the inferred immune pathway activities were different in the brains of TSC patients with early vs late onset of epilepsy.
Conclusions:
The results together suggest that the immune system plays an important role in epilepsy age of onset in TSC. Both genetic and environmental factors affect the molecular state of the immune system in the brain. Routine brain biopsy of TSC patients is impractical, thus whole genome sequencing or whole exome sequencing beyond sequencing TSC1 and TSC2 is necessary to infer immune system activity in the brain of TSC patients and critical to develop personalized medicine for TSC patients.
REFERENCES
1. Henske EP, Jozwiak S, Kingswood JC, et al. Nat Rev Dis Primers 2016;2:16035.
2. Aronica E, Specchio N, Luinenburg MJ, et al. Brain 2023; awad048.
3. Mills JD, Iyer AM, van Scheppingen J, et al. Sci Rep 2017;7:8089.
Funding: None