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Ultra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II

 Ja Hye Kim  ;  Ji-Hyung Park  ;  Junehawk Lee  ;  Jung Woo Park  ;  Hyun Jung Kim  ;  Won Seok Chang  ;  Dong-Seok Kim  ;  Young Seok Ju  ;  Eleonora Aronica  ;  Jeong Ho Lee 
 ANNALS OF NEUROLOGY, Vol.93(6) : 1082-1093, 2023-06 
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Epilepsy* / genetics ; Focal Cortical Dysplasia* ; Humans ; Mutation / genetics ; TOR Serine-Threonine Kinases / genetics
Objective: Brain somatic mutations in mTOR pathway genes are a major genetic etiology of focal cortical dysplasia type II (FCDII). Despite a greater ability to detect low-level somatic mutations in the brain by deep sequencing and analytics, about 40% of cases remain genetically unexplained. Methods: We included 2 independent cohorts consisting of 21 patients with mutation-negative FCDII without apparent mutations on conventional deep sequencing of bulk brain. To find ultra-low level somatic variants or structural variants, we isolated cells exhibiting phosphorylation of the S6 ribosomal protein (p-S6) in frozen brain tissues using fluorescence-activated cell sorting (FACS). We then performed deep whole-genome sequencing (WGS; > 90x) in p-S6(+) cells in a cohort of 11 patients with mutation-negative. Then, we simplified the method to whole-genome amplification and target gene sequencing of p-S6(+) cells in independent cohort of 10 patients with mutation-negative followed by low-read depth WGS (10x). Results We found that 28.6% (6 of 21) of mutation-negative FCDII carries ultra-low level somatic mutations (less than 0.2% of variant allele frequency [VAF]) in mTOR pathway genes. Our method showed similar to 34 times increase of the average mutational burden in FACS mediated enrichment of p-S6(+) cells (average VAF = 5.84%) than in bulky brain tissues (average VAF = 0.17%). We found that 19% (4 of 21) carried germline structural variations in GATOR1 complex undetectable in whole exome or targeted gene sequencing. Conclusions: Our method facilitates the detection of ultra-low level somatic mutations, in specifically p-S6(+) cells, and germline structural variations and increases the genetic diagnostic rate up to similar to 80% for the entire FCDII cohort.
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1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Seok(김동석)
Chang, Won Seok(장원석) ORCID logo https://orcid.org/0000-0003-3145-4016
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