Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
received:
06
04
2022
accepted:
30
11
2022
pubmed:
13
1
2023
medline:
16
2
2023
entrez:
12
1
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36635388
doi: 10.1038/s41588-022-01276-9
pii: 10.1038/s41588-022-01276-9
pmc: PMC9961399
mid: NIHMS1869042
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
209-220Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH124890
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS047101
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG006504
Pays : United States
Organisme : NIH HHS
ID : S10 OD026929
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS120854
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG003067
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH108898
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG070462
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS083823
Pays : United States
Investigateurs
Joseph G Gleeson
(JG)
Marilyn Jones
(M)
Diane Masser-Frye
(D)
Shifteh Sattar
(S)
Mark Nespeca
(M)
David D Gonda
(DD)
Katsumi Imai
(K)
Yukitoshi Takahashi
(Y)
Hsin-Hung Chen
(HH)
Jin-Wu Tsai
(JW)
Valerio Conti
(V)
Renzo Guerrini
(R)
Orrin Devinsky
(O)
Helio R Machado
(HR)
Camila Araújo Bernardino Garcia
(CAB)
Wilson A Silva
(WA)
Se Hoon Kim
(SH)
Hoon-Chul Kang
(HC)
Yasemin Alanay
(Y)
Seema Kapoor
(S)
Carola A Haas
(CA)
Georgia Ramantani
(G)
Thomas Feuerstein
(T)
Ingmar Blumcke
(I)
Robyn Busch
(R)
Zhong Ying
(Z)
Vadym Biloshytsky
(V)
Kostiantyn Kostiuk
(K)
Eugene Pedachenko
(E)
Gary W Mathern
(GW)
Christina A Gurnett
(CA)
Matthew D Smyth
(MD)
Ingo Helbig
(I)
Benjamin C Kennedy
(BC)
Judy Liu
(J)
Felix Chan
(F)
Darcy Krueger
(D)
Richard Frye
(R)
Angus Wilfong
(A)
David Adelson
(D)
William Gaillard
(W)
Chima Oluigbo
(C)
Anne Anderson
(A)
Alice Lee
(A)
August Yue Huang
(AY)
Alissa D'Gama
(A)
Caroline Dias
(C)
Christopher A Walsh
(CA)
Eduardo Maury
(E)
Javier Ganz
(J)
Michael Lodato
(M)
Michael Miller
(M)
Pengpeng Li
(P)
Rachel Rodin
(R)
Rebeca Borges-Monroy
(R)
Robert Hill
(R)
Sara Bizzotto
(S)
Sattar Khoshkhoo
(S)
Sonia Kim
(S)
Zinan Zhou
(Z)
Alice Lee
(A)
Alison Barton
(A)
Alon Galor
(A)
Chong Chu
(C)
Craig Bohrson
(C)
Doga Gulhan
(D)
Eduardo Maury
(E)
Elaine Lim
(E)
Euncheon Lim
(E)
Giorgio Melloni
(G)
Isidro Cortes
(I)
Jake Lee
(J)
Joe Luquette
(J)
Lixing Yang
(L)
Maxwell Sherman
(M)
Michael Coulter
(M)
Minseok Kwon
(M)
Peter J Park
(PJ)
Rebeca Borges-Monroy
(R)
Semin Lee
(S)
Sonia Kim
(S)
Soo Lee
(S)
Vinary Viswanadham
(V)
Yanmei Dou
(Y)
Andrew J Chess
(AJ)
Attila Jones
(A)
Chaggai Rosenbluh
(C)
Schahram Akbarian
(S)
Ben Langmead
(B)
Jeremy Thorpe
(J)
Sean Cho
(S)
Andrew Jaffe
(A)
Apua Paquola
(A)
Daniel Weinberger
(D)
Jennifer Erwin
(J)
Jooheon Shin
(J)
Michael McConnell
(M)
Richard Straub
(R)
Rujuta Narurkar
(R)
Alexej Abyzov
(A)
Taejeong Bae
(T)
Yeongjun Jang
(Y)
Yifan Wang
(Y)
Anjene Addington
(A)
Geetha Senthil
(G)
Cindy Molitor
(C)
Mette Peters
(M)
Fred H Gage
(FH)
Meiyan Wang
(M)
Patrick Reed
(P)
Sara Linker
(S)
Alexander Urban
(A)
Bo Zhou
(B)
Reenal Pattni
(R)
Xiaowei Zhu
(X)
Aitor Serres Amero
(AS)
David Juan
(D)
Inna Povolotskaya
(I)
Irene Lobon
(I)
Manuel Solis Moruno
(MS)
Raquel Garcia Perez
(RG)
Tomas Marques-Bonet
(T)
Eduardo Soriano
(E)
Gary Mathern
(G)
Danny Antaki
(D)
Dan Averbuj
(D)
Eric Courchesne
(E)
Joseph G Gleeson
(JG)
Laurel L Ball
(LL)
Martin W Breuss
(MW)
Subhojit Roy
(S)
Xiaoxu Yang
(X)
Changuk Chung
(C)
Chen Sun
(C)
Diane A Flasch
(DA)
Trenton J Frisbie Trenton
(TJF)
Huira C Kopera
(HC)
Jeffrey M Kidd
(JM)
John B Moldovan
(JB)
John V Moran
(JV)
Kenneth Y Kwan
(KY)
Ryan E Mills
(RE)
Sarah B Emery
(SB)
Weichen Zhou
(W)
Xuefang Zhao
(X)
Aakrosh Ratan
(A)
Adriana Cherskov
(A)
Alexandre Jourdon
(A)
Flora M Vaccarino
(FM)
Liana Fasching
(L)
Nenad Sestan
(N)
Sirisha Pochareddy
(S)
Soraya Scuder
(S)
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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