DC Field | Value | Language |
---|---|---|
dc.contributor.author | Kim, Ja Hye | ko |
dc.contributor.author | Park, Ji-Hyung | ko |
dc.contributor.author | Lee, Junehawk | ko |
dc.contributor.author | Park, Jung Woo | ko |
dc.contributor.author | Kim, Hyun Jung | ko |
dc.contributor.author | Chang, Won Seok | ko |
dc.contributor.author | Kim, Dong-Seok | ko |
dc.contributor.author | Ju, Young Seok | ko |
dc.contributor.author | Aronica, Eleonora | ko |
dc.contributor.author | Lee, Jeong Ho | ko |
dc.date.accessioned | 2023-06-16T06:01:44Z | - |
dc.date.available | 2023-06-16T06:01:44Z | - |
dc.date.created | 2023-03-13 | - |
dc.date.issued | 2023-06 | - |
dc.identifier.citation | ANNALS OF NEUROLOGY, v.93, no.6, pp.1082 - 1093 | - |
dc.identifier.issn | 0364-5134 | - |
dc.identifier.uri | http://hdl.handle.net/10203/307310 | - |
dc.description.abstract | 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. | - |
dc.language | English | - |
dc.publisher | WILEY | - |
dc.title | Ultra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II | - |
dc.type | Article | - |
dc.identifier.wosid | 000931231400001 | - |
dc.identifier.scopusid | 2-s2.0-85147592408 | - |
dc.type.rims | ART | - |
dc.citation.volume | 93 | - |
dc.citation.issue | 6 | - |
dc.citation.beginningpage | 1082 | - |
dc.citation.endingpage | 1093 | - |
dc.citation.publicationname | ANNALS OF NEUROLOGY | - |
dc.identifier.doi | 10.1002/ana.26609 | - |
dc.contributor.localauthor | Ju, Young Seok | - |
dc.contributor.localauthor | Lee, Jeong Ho | - |
dc.contributor.nonIdAuthor | Lee, Junehawk | - |
dc.contributor.nonIdAuthor | Park, Jung Woo | - |
dc.contributor.nonIdAuthor | Kim, Hyun Jung | - |
dc.contributor.nonIdAuthor | Chang, Won Seok | - |
dc.contributor.nonIdAuthor | Kim, Dong-Seok | - |
dc.contributor.nonIdAuthor | Aronica, Eleonora | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordPlus | EPILEPSY SURGERY | - |
dc.subject.keywordPlus | BRAIN-TISSUE | - |
dc.subject.keywordPlus | TASK-FORCE | - |
dc.subject.keywordPlus | PATHWAY | - |
dc.subject.keywordPlus | ACTIVATION | - |
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