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

被引：30

作者：

Chung, Changuk ^{[1
,2
]}

Yang, Xiaoxu ^{[1
,2
]}

Bae, Taejeong ^{[3
]}

Vong, Keng Ioi ^{[1
,2
]}

Mittal, Swapnil H. ^{[1
,2
]}

Donkels, Catharina ^{[4
]}

Westley Phillips, H. ^{[5
]}

Li, Zhen ^{[1
,2
]}

Marsh, Ashley P. L. ^{[1
,2
]}

Breuss, Martin ^{[1
,2
,6
]}

Ball, Laurel ^{[1
,2
]}

Garcia, Camila Araujo Bernardino ^{[7
]}

George, Renee ^{[1
,2
]}

Gu, Jing ^{[1
,2
]}

Xu, Mingchu ^{[1
,2
]}

Barrows, Chelsea ^{[1
,2
]}

James, Kiely ^{[1
,2
]}

Stanley, Valentina ^{[1
,2
]}

Nidhiry, Anna ^{[1
,2
]}

Khoury, Sami ^{[1
,2
]}

Howe, Gabrielle ^{[1
,2
]}

Riley, Emily ^{[1
,2
]}

Xu, Xin ^{[1
,2
]}

Copeland, Brett ^{[1
,2
]}

Wang, Yifan G.

Kim, Se Hoon L. ^{[8
]}

Kang, Hoon-Chul W. ^{[9
]}

Schulze-Bonhage, Andreas ^{[10
]}

Haas, Carola ^{[10
]}

Urbach, Horst ^{[11
]}

Prinz, Marco ^{[10
,12
,13
,14
]}

Limbrick, David A. ^{[15
]}

Gurnett, Christina ^{[15
]}

Smyth, Matthew C. ^{[16
]}

Sattar, Shifteh M. ^{[17
]}

Nespeca, Mark B. ^{[17
]}

Gonda, David V. ^{[17
]}

Imai, Katsumi Y. ^{[18
]}

Takahashi, Yukitoshi E. ^{[18
]}

Chen, Hsin-Hung B. ^{[19
]}

Tsai, Jin-Wu ^{[20
]}

Conti, Valerio ^{[21
]}

Guerrini, Renzo ^{[21
]}

Devinsky, Orrin ^{[22
]}

Silva, Wilson ^{[23
]}

Machado, Helio M. ^{[7
]}

Mathern, Gary ^{[5
]}

Abyzov, Alexej ^{[3
]}

Baldassari, Sara ^{[24
]}

Baulac, Stephanie ^{[24
]}

机构：

[1] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[2] Rady Childrens Inst Genom Med, San Diego, CA 92123 USA

[3] Mayo Clin, Ctr Individualized Med, Dept Quantitat Hlth Sci, Rochester, MN USA

[4] Univ Freiburg, Fac Med, Med Ctr, Dept Neurosurg, Freiburg, Germany

[5] Univ Calif Los Angeles, Dept Neurosurg, Los Angeles, CA USA

[6] Univ Colorado Aurora, Dept Pediat, Sect Clin Genet & Metab, Aurora, CO USA

[7] Univ Sao Paulo, Dept Surg & Anat, Lab Pediat Neurosurg & Dev Neuropathol, Ribeirao Preto, Brazil

[8] Yonsei Univ, Severance Hosp, Coll Med, Dept Pathol, Seoul, South Korea

[9] Yonsei Univ, Severance Childrens Hosp, Coll Med, Dept Pediat,Div Pediat Neurol, Seoul, South Korea

[10] Univ Freiburg, Fac Med, Ctr Basics NeuroModulat, Freiburg, Germany

[11] Univ Freiburg, Fac Med, Med Ctr, Dept Neuroradiol, Freiburg, Germany

[12] Univ Freiburg, Inst Neuropathol, Fac Med, Med Ctr, Freiburg, Germany

[13] Univ Freiburg, Signalling Res Ctr BIOSS, Freiburg, Germany

[14] Univ Freiburg, CIBSS, Freiburg, Germany

[15] Washington Univ St Louis, St Louis Childrens Hosp, Dept Neurol, Washington, MO USA

[16] Washington Univ St Louis, St Louis Childrens Hosp, Dept Neurosurg, Washington, MO USA

[17] Rady Childrens Hosp, Epilepsy Ctr, San Diego, CA USA

[18] NHO Shizuoka Inst Epilepsy & Neurol Disorders, Natl Epilepsy Ctr, Shizuoka, Japan

[19] Taipei Vet Gen Hosp, Neurol Inst, Div Pediat Neurosurg, Taipei, Taiwan

[20] Natl Yang Ming Chiao Tung Univ, Inst Brain Sci, Brain Res Ctr, Taipei, Taiwan

[21] Univ Florence, IRCCS Meyer Childrens Hosp, Pediat Neurol Unit & Labs, Florence, Italy

[22] New York Univ Langone Hlth, Comprehens Epilepsy Ctr, Dept Neurol, New York, NY USA

[23] Univ Sao Paulo, Ctr Cell Based Therapy, Ctr Integrat Syst Biol, Dept Genet, Ribeirao Preto, Brazil

[24] Sorbonne Univ, Hop Pitie Salpetriere, Paris Brain Inst, Inst Cerveau,ICM,Inserm,CNRS, Paris, France

来源：

NATURE GENETICS | 2023年 / 55卷 / 02期

关键词：

GENE-EXPRESSION; DYSPLASIA; PATHWAY; DIFFERENTIATION; PLASTICITY; MIGRATION; EPILEPSY; SPECTRUM; IMPACT;

D O I：

10.1038/s41588-022-01276-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：209 / +

页数：32

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[1] Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
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