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Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.


ABSTRACT: 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. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

SUBMITTER: Chung C 

PROVIDER: S-EPMC9961399 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.

Chung Changuk C   Yang Xiaoxu X   Bae Taejeong T   Vong Keng Ioi KI   Mittal Swapnil S   Donkels Catharina C   Westley Phillips H H   Li Zhen Z   Marsh Ashley P L APL   Breuss Martin W MW   Ball Laurel L LL   Garcia Camila Araújo Bernardino CAB   George Renee D RD   Gu Jing J   Xu Mingchu M   Barrows Chelsea C   James Kiely N KN   Stanley Valentina V   Nidhiry Anna S AS   Khoury Sami S   Howe Gabrielle G   Riley Emily E   Xu Xin X   Copeland Brett B   Wang Yifan Y   Kim Se Hoon SH   Kang Hoon-Chul HC   Schulze-Bonhage Andreas A   Haas Carola A CA   Urbach Horst H   Prinz Marco M   Limbrick David D DD   Gurnett Christina A CA   Smyth Matthew D MD   Sattar Shifteh S   Nespeca Mark M   Gonda David D DD   Imai Katsumi K   Takahashi Yukitoshi Y   Chen Hsin-Hung HH   Tsai Jin-Wu JW   Conti Valerio V   Guerrini Renzo R   Devinsky Orrin O   Silva Wilson A WA   Machado Helio R HR   Mathern Gary W GW   Abyzov Alexej A   Baldassari Sara S   Baulac Stéphanie S   Gleeson Joseph G JG  

Nature genetics 20230112 2


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 m  ...[more]

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