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

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dc.contributor.authorKim, Ja Hyeko
dc.contributor.authorPark, Ji-Hyungko
dc.contributor.authorLee, Junehawkko
dc.contributor.authorPark, Jung Wooko
dc.contributor.authorKim, Hyun Jungko
dc.contributor.authorChang, Won Seokko
dc.contributor.authorKim, Dong-Seokko
dc.contributor.authorJu, Young Seokko
dc.contributor.authorAronica, Eleonorako
dc.contributor.authorLee, Jeong Hoko
dc.date.accessioned2023-06-16T06:01:44Z-
dc.date.available2023-06-16T06:01:44Z-
dc.date.created2023-03-13-
dc.date.issued2023-06-
dc.identifier.citationANNALS OF NEUROLOGY, v.93, no.6, pp.1082 - 1093-
dc.identifier.issn0364-5134-
dc.identifier.urihttp://hdl.handle.net/10203/307310-
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.languageEnglish-
dc.publisherWILEY-
dc.titleUltra-Low Level Somatic Mutations and Structural Variations in Focal Cortical Dysplasia Type II-
dc.typeArticle-
dc.identifier.wosid000931231400001-
dc.identifier.scopusid2-s2.0-85147592408-
dc.type.rimsART-
dc.citation.volume93-
dc.citation.issue6-
dc.citation.beginningpage1082-
dc.citation.endingpage1093-
dc.citation.publicationnameANNALS OF NEUROLOGY-
dc.identifier.doi10.1002/ana.26609-
dc.contributor.localauthorJu, Young Seok-
dc.contributor.localauthorLee, Jeong Ho-
dc.contributor.nonIdAuthorLee, Junehawk-
dc.contributor.nonIdAuthorPark, Jung Woo-
dc.contributor.nonIdAuthorKim, Hyun Jung-
dc.contributor.nonIdAuthorChang, Won Seok-
dc.contributor.nonIdAuthorKim, Dong-Seok-
dc.contributor.nonIdAuthorAronica, Eleonora-
dc.description.isOpenAccessN-
dc.type.journalArticleArticle-
dc.subject.keywordPlusEPILEPSY SURGERY-
dc.subject.keywordPlusBRAIN-TISSUE-
dc.subject.keywordPlusTASK-FORCE-
dc.subject.keywordPlusPATHWAY-
dc.subject.keywordPlusACTIVATION-
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