[Title]
Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy

[Author]

Jintae Kim,1 Sang Min Park,1,2 Hyun Yong Koh,3 Ara Ko,1,4 Hoon-Chul Kang,5 Won Seok Chang,5 Dong Seok Kim5 and Jeong Ho Lee1,2

1 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
2 SoVarGen Co., Ltd., Daejeon, Republic of Korea
3 Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, USA 
4 Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea 
5 Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea

Correspondence to : Jeong Ho Lee 
KAIST BioMedical Research Center, Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of 6 Korea 7

[Journal] 

Brain, awae190, https://doi.org/10.1093/brain/awae190 (25 June 2024)


[Abstract]

Somatic mosaicism in a fraction of brain cells causes neurodevelopmental disorders, including childhood intractable epilepsy. However, the threshold for somatic mosaicism leading to brain dysfunction is unknown. In this study, we induced various mosaic burdens in focal cortical dysplasia type II (FCD II) mice, featuring mTOR somatic mosaicism and spontaneous behavioral seizures. The mosaic burdens ranged from approximately 1,000 to 40,000 neurons expressing the mTOR mutant in the somatosensory (SSC) or medial prefrontal (PFC) cortex. Surprisingly, approximately 8,000 to 9,000 neurons expressing the MTOR mutant, which are extrapolated to constitute 0.08-0.09% of total cells or roughly 0.04% of variant allele frequency (VAF) in the mouse hemicortex, were sufficient to trigger epileptic seizures. The mutational burden was correlated with seizure frequency and onset, with a higher tendency for electrographic inter-ictal spikes and beta- and gamma-frequency oscillations in FCD II mice exceeding the threshold. Moreover, mutation-negative FCD II patients in deep sequencing of their bulky brain tissues revealed somatic mosaicism of the mTOR pathway genes as low as 0.07% in resected brain tissues through ultra-deep targeted sequencing (up to 20 million reads). Thus, our study suggests that extremely low levels of somatic mosaicism can contribute to brain dysfunction.