RT Journal Article
SR Electronic
T1 Comprehensive multiomic profiling of somatic mutations in malformations of cortical development
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.07.487401
DO 10.1101/2022.04.07.487401
A1 Changuk Chung
A1 Xiaoxu Yang
A1 Taejeong Bae
A1 Keng Ioi Vong
A1 Swapnil Mittal
A1 Catharina Donkels
A1 H. Westley Phillips
A1 Ashley P. L. Marsh
A1 Martin W. Breuss
A1 Laurel L. Ball
A1 Camila Araújo Bernardino Garcia
A1 Renee D. George
A1 Jing Gu
A1 Mingchu Xu
A1 Chelsea Barrows
A1 Kiely N. James
A1 Valentina Stanley
A1 Anna Nidhiry
A1 Sami Khoury
A1 Gabrielle Howe
A1 Emily Riley
A1 Xin Xu
A1 Brett Copeland
A1 Yifan Wang
A1 Se Hoon Kim
A1 Hoon-Chul Kang
A1 Andreas Schulze-Bonhage
A1 Carola A. Haas
A1 Horst Urbach
A1 Marco Prinz
A1 Corrine Gardner
A1 Christina A. Gurnett
A1 Shifteh Sattar
A1 Mark Nespeca
A1 David D. Gonda
A1 Katsumi Imai
A1 Yukitoshi Takahashi
A1 Robert Chen
A1 Jin-Wu Tsai
A1 Valerio Conti
A1 Renzo Guerrini
A1 Orrin Devinsky
A1 Wilson A. Silva, Jr
A1 Helio R. Machado
A1 Gary W. Mathern
A1 Alexej Abyzov
A1 Sara Baldassari
A1 Stéphanie Baulac
A1 Focal Cortical Dysplasia Neurogenetics Consortium
A1 Brain Somatic Mosaicism Network
A1 Joseph G. Gleeson
YR 2022
UL http://biorxiv.org/content/early/2022/04/11/2022.04.07.487401.abstract
AB Malformations of cortical development (MCD) are neurological conditions displaying focal disruption of cortical architecture and cellular organization arising during embryogenesis, largely from somatic mosaic mutations. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat epilepsy. Here, we report a genetic atlas from 317 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation and single-cell sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associating distinct pathophysiological and clinical phenotypes. The unique spatiotemporal expression patterns identified by comparing single-nucleus transcriptional sequences of mutated genes in control and patient brains implicate critical roles in excitatory neurogenic pools during brain development, and in promoting neuronal hyperexcitability after birth.Competing Interest StatementThe authors have declared no competing interest.