Changuk Chung, Xiaoxu Yang, Taejeong Bae, Keng Ioi Vong, Swapnil Mittal, Catharina Donkels, H Westley Phillips, Zhen Li, Ashley P L Marsh, Martin W Breuss, Laurel L Ball, Camila Araújo Bernardino Garcia, Renee D George, Jing Gu, Mingchu Xu, Chelsea Barrows, Kiely N James, Valentina Stanley, Anna S Nidhiry, Sami Khoury, Gabrielle Howe, Emily Riley, Xin Xu, Brett Copeland, Yifan Wang, Se Hoon Kim, Hoon-Chul Kang, Andreas Schulze-Bonhage, Carola A Haas, Horst Urbach, Marco Prinz, David D Limbrick, Christina A Gurnett, Matthew D Smyth, Shifteh Sattar, Mark Nespeca, David D Gonda, Katsumi Imai, Yukitoshi Takahashi, Hsin-Hung Chen, Jin-Wu Tsai, Valerio Conti, Renzo Guerrini, Orrin Devinsky, Wilson A Silva, Helio R Machado, Gary W Mathern, Alexej Abyzov, Sara Baldassari, Stéphanie Baulac, Joseph G Gleeson
Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing...
February 2023: Nature Genetics