Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
Changuk Chung
(1, 2)
,
Xiaoxu Yang
(1, 2)
,
Taejeong Bae
(3)
,
Keng Ioi Vong
(1, 2)
,
Swapnil Mittal
(1, 2)
,
Catharina Donkels
(4)
,
H. Westley Phillips
(5)
,
Zhen Li
(1, 2)
,
Ashley P L Marsh
(1, 2)
,
Martin W Breuss
(1, 2)
,
Laurel L Ball
(1, 2)
,
Camila Araújo Bernardino Garcia
(6)
,
Renee D George
(1, 2)
,
Jing Gu
(1, 2)
,
Mingchu Xu
(1, 2)
,
Chelsea Barrows
(1, 2)
,
Kiely N James
(1, 2)
,
Valentina Stanley
(1, 2)
,
Anna S Nidhiry
(1, 2)
,
Sami Khoury
(1, 2)
,
Gabrielle Howe
(1, 2)
,
Emily Riley
(1, 2)
,
Xin Xu
(1, 2)
,
Brett Copeland
(1, 2)
,
Yifan Wang
(3)
,
Se Hoon Kim
(7)
,
Hoon-Chul Kang
(7)
,
Andreas Schulze-Bonhage
(4)
,
Carola A Haas
(4)
,
Horst Urbach
(8)
,
Marco Prinz
(8, 4)
,
David D Limbrick
(9, 10)
,
Christina A Gurnett
(9, 10)
,
Matthew D Smyth
(9, 10)
,
Shifteh Sattar
(11)
,
Mark Nespeca
(11)
,
David D Gonda
(11)
,
Katsumi Imai
(12)
,
Yukitoshi Takahashi
(12)
,
Hsin-Hung Chen
(13)
,
Jin-Wu Tsai
(14)
,
Valerio Conti
(15, 16)
,
Renzo Guerrini
(15, 16)
,
Orrin Devinsky
(17)
,
Wilson A Silva
(6)
,
Helio R Machado
(6)
,
Gary W Mathern
(5)
,
Alexej Abyzov
(3)
,
Sara Baldassari
(18, 19)
,
Stéphanie Baulac
(18, 19)
,
Joseph G Gleeson
(1, 2)
1
UC San Diego -
University of California [San Diego]
2 Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
3 Mayo Clinic [Rochester]
4 Albert-Ludwigs-Universität Freiburg = University of Freiburg
5 UCLA - University of California [Los Angeles]
6 USP - Universidade de São Paulo = University of São Paulo
7 Yonsei University
8 Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
9 St. Louis Children's Hospital
10 WUSTL - Washington University in Saint Louis
11 Rady Children's Hospital
12 University of Shizuoka
13 Taipei Veterans General Hospital [Taiwan]
14 NYCU - National Yang Ming Chiao Tung University [Taipei]
15 AOU Meyer - Azienda Ospedaliero Universitaria Meyer [Firenze] = Meyer Children's University Hospital [Florence]
16 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
17 NYU Langone Medical Center - New York University Langone Medical Center
18 ICM - Institut du Cerveau = Paris Brain Institute
19 CHU Pitié-Salpêtrière [AP-HP]
2 Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA]
3 Mayo Clinic [Rochester]
4 Albert-Ludwigs-Universität Freiburg = University of Freiburg
5 UCLA - University of California [Los Angeles]
6 USP - Universidade de São Paulo = University of São Paulo
7 Yonsei University
8 Uniklinik - Universitäts Klinikum Freiburg = University Medical Center Freiburg
9 St. Louis Children's Hospital
10 WUSTL - Washington University in Saint Louis
11 Rady Children's Hospital
12 University of Shizuoka
13 Taipei Veterans General Hospital [Taiwan]
14 NYCU - National Yang Ming Chiao Tung University [Taipei]
15 AOU Meyer - Azienda Ospedaliero Universitaria Meyer [Firenze] = Meyer Children's University Hospital [Florence]
16 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
17 NYU Langone Medical Center - New York University Langone Medical Center
18 ICM - Institut du Cerveau = Paris Brain Institute
19 CHU Pitié-Salpêtrière [AP-HP]
Xiaoxu Yang
- Fonction : Auteur
- PersonId : 1391668
- ORCID : 0000-0003-0219-0023
Keng Ioi Vong
- Fonction : Auteur
- PersonId : 1391669
- ORCID : 0000-0001-5377-9845
Catharina Donkels
- Fonction : Auteur
- PersonId : 1391670
- ORCID : 0000-0003-2636-3873
H. Westley Phillips
- Fonction : Auteur
- PersonId : 1391671
- ORCID : 0000-0003-0512-4590
Marco Prinz
- Fonction : Auteur
- PersonId : 1391674
- ORCID : 0000-0002-0349-1955
Matthew D Smyth
- Fonction : Auteur
Hsin-Hung Chen
- Fonction : Auteur
- PersonId : 1391675
- ORCID : 0000-0001-7531-9188
Wilson A Silva
- Fonction : Auteur
- PersonId : 805347
- ORCID : 0000-0001-9364-2886
Alexej Abyzov
- Fonction : Auteur
- PersonId : 1391676
- ORCID : 0000-0001-5405-6729
Résumé
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, and causing 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 associating distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns 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.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers produits par l'(les) auteur(s) |
|---|---|
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