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

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dc.contributor.author김동석-
dc.contributor.author장원석-
dc.date.accessioned2024-05-30T07:01:48Z-
dc.date.available2024-05-30T07:01:48Z-
dc.date.issued2023-06-
dc.identifier.issn0364-5134-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/199518-
dc.description.abstractObjective: 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.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherWiley-Liss-
dc.relation.isPartOfANNALS OF NEUROLOGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHEpilepsy* / genetics-
dc.subject.MESHFocal Cortical Dysplasia*-
dc.subject.MESHHumans-
dc.subject.MESHMutation / genetics-
dc.subject.MESHTOR Serine-Threonine Kinases / genetics-
dc.titleUltra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Neurosurgery (신경외과학교실)-
dc.contributor.googleauthorJa Hye Kim-
dc.contributor.googleauthorJi-Hyung Park-
dc.contributor.googleauthorJunehawk Lee-
dc.contributor.googleauthorJung Woo Park-
dc.contributor.googleauthorHyun Jung Kim-
dc.contributor.googleauthorWon Seok Chang-
dc.contributor.googleauthorDong-Seok Kim-
dc.contributor.googleauthorYoung Seok Ju-
dc.contributor.googleauthorEleonora Aronica-
dc.contributor.googleauthorJeong Ho Lee-
dc.identifier.doi10.1002/ana.26609-
dc.contributor.localIdA00402-
dc.contributor.localIdA03454-
dc.relation.journalcodeJ00166-
dc.identifier.eissn1531-8249-
dc.identifier.pmid36700525-
dc.identifier.urlhttps://onlinelibrary.wiley.com/doi/10.1002/ana.26609-
dc.contributor.alternativeNameKim, Dong Seok-
dc.contributor.affiliatedAuthor김동석-
dc.contributor.affiliatedAuthor장원석-
dc.citation.volume93-
dc.citation.number6-
dc.citation.startPage1082-
dc.citation.endPage1093-
dc.identifier.bibliographicCitationANNALS OF NEUROLOGY, Vol.93(6) : 1082-1093, 2023-06-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers

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