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Ultra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II
DC Field | Value | Language |
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dc.contributor.author | 김동석 | - |
dc.contributor.author | 장원석 | - |
dc.date.accessioned | 2024-05-30T07:01:48Z | - |
dc.date.available | 2024-05-30T07:01:48Z | - |
dc.date.issued | 2023-06 | - |
dc.identifier.issn | 0364-5134 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/199518 | - |
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.description.statementOfResponsibility | restriction | - |
dc.language | English | - |
dc.publisher | Wiley-Liss | - |
dc.relation.isPartOf | ANNALS OF NEUROLOGY | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.subject.MESH | Epilepsy* / genetics | - |
dc.subject.MESH | Focal Cortical Dysplasia* | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | Mutation / genetics | - |
dc.subject.MESH | TOR Serine-Threonine Kinases / genetics | - |
dc.title | Ultra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine (의과대학) | - |
dc.contributor.department | Dept. of Neurosurgery (신경외과학교실) | - |
dc.contributor.googleauthor | Ja Hye Kim | - |
dc.contributor.googleauthor | Ji-Hyung Park | - |
dc.contributor.googleauthor | Junehawk Lee | - |
dc.contributor.googleauthor | Jung Woo Park | - |
dc.contributor.googleauthor | Hyun Jung Kim | - |
dc.contributor.googleauthor | Won Seok Chang | - |
dc.contributor.googleauthor | Dong-Seok Kim | - |
dc.contributor.googleauthor | Young Seok Ju | - |
dc.contributor.googleauthor | Eleonora Aronica | - |
dc.contributor.googleauthor | Jeong Ho Lee | - |
dc.identifier.doi | 10.1002/ana.26609 | - |
dc.contributor.localId | A00402 | - |
dc.contributor.localId | A03454 | - |
dc.relation.journalcode | J00166 | - |
dc.identifier.eissn | 1531-8249 | - |
dc.identifier.pmid | 36700525 | - |
dc.identifier.url | https://onlinelibrary.wiley.com/doi/10.1002/ana.26609 | - |
dc.contributor.alternativeName | Kim, Dong Seok | - |
dc.contributor.affiliatedAuthor | 김동석 | - |
dc.contributor.affiliatedAuthor | 장원석 | - |
dc.citation.volume | 93 | - |
dc.citation.number | 6 | - |
dc.citation.startPage | 1082 | - |
dc.citation.endPage | 1093 | - |
dc.identifier.bibliographicCitation | ANNALS OF NEUROLOGY, Vol.93(6) : 1082-1093, 2023-06 | - |
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