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

Cited 6 time in webofscience Cited 0 time in scopus
  • Hit : 126
  • Download : 0
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.
Publisher
WILEY
Issue Date
2023-06
Language
English
Article Type
Article
Citation

ANNALS OF NEUROLOGY, v.93, no.6, pp.1082 - 1093

ISSN
0364-5134
DOI
10.1002/ana.26609
URI
http://hdl.handle.net/10203/307310
Appears in Collection
MSE-Journal Papers(저널논문)
Files in This Item
There are no files associated with this item.
This item is cited by other documents in WoS
⊙ Detail Information in WoSⓡ Click to see webofscience_button
⊙ Cited 6 items in WoS Click to see citing articles in records_button

qr_code

  • mendeley

    citeulike


rss_1.0 rss_2.0 atom_1.0