De novo mutations in epileptic encephalopathies.
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.
Andrew S
AS
Allen
Samuel F
SF
Berkovic
Patrick
P
Cossette
Norman
N
Delanty
Dennis
D
Dlugos
Evan E
EE
Eichler
Michael P
MP
Epstein
Tracy
T
Glauser
David B
DB
Goldstein
Yujun
Y
Han
Erin L
EL
Heinzen
Yuki
Y
Hitomi
Katherine B
KB
Howell
Michael R
MR
Johnson
Ruben
R
Kuzniecky
Daniel H
DH
Lowenstein
Yi-Fan
YF
Lu
Maura R Z
MR
Madou
Anthony G
AG
Marson
Heather C
HC
Mefford
Sahar
S
Esmaeeli Nieh
Terence J
TJ
O'Brien
Ruth
R
Ottman
Slavé
S
Petrovski
Annapurna
A
Poduri
Elizabeth K
EK
Ruzzo
Ingrid E
IE
Scheffer
Elliott H
EH
Sherr
Christopher J
CJ
Yuskaitis
Bassel
B
Abou-Khalil
Brian K
BK
Alldredge
Jocelyn F
JF
Bautista
Samuel F
SF
Berkovic
Alex
A
Boro
Gregory D
GD
Cascino
Damian
D
Consalvo
Patricia
P
Crumrine
Orrin
O
Devinsky
Dennis
D
Dlugos
Michael P
MP
Epstein
Miguel
M
Fiol
Nathan B
NB
Fountain
Jacqueline
J
French
Daniel
D
Friedman
Eric B
EB
Geller
Tracy
T
Glauser
Simon
S
Glynn
Sheryl R
SR
Haut
Jean
J
Hayward
Sandra L
SL
Helmers
Sucheta
S
Joshi
Andres
A
Kanner
Heidi E
HE
Kirsch
Robert C
RC
Knowlton
Eric H
EH
Kossoff
Rachel
R
Kuperman
Ruben
R
Kuzniecky
Daniel H
DH
Lowenstein
Shannon M
SM
McGuire
Paul V
PV
Motika
Edward J
EJ
Novotny
Ruth
R
Ottman
Juliann M
JM
Paolicchi
Jack M
JM
Parent
Kristen
K
Park
Annapurna
A
Poduri
Ingrid E
IE
Scheffer
Renée A
RA
Shellhaas
Elliott H
EH
Sherr
Jerry J
JJ
Shih
Rani
R
Singh
Joseph
J
Sirven
Michael C
MC
Smith
Joseph
J
Sullivan
Liu
L
Lin Thio
Anu
A
Venkat
Eileen P G
EP
Vining
Gretchen K
GK
Von Allmen
Judith L
JL
Weisenberg
Peter
P
Widdess-Walsh
Melodie R
MR
Winawer
D002659:Child Development Disorders, Pervasive; D015331:Cohort Studies; D059472:Exome / Q000235:genetics; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D065768:Lennox Gastaut Syndrome; D008297:Male; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D011336:Probability; D011963:Receptors, GABA-A / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics* / Q000503:physiopathology
D051860:Fragile X Messenger Ribonucleoprotein 1; D017351:N-Acetylglucosaminyltransferases; D011963:Receptors, GABA-A; C497683:FMR1 protein, human; C546273:GABRB3 protein, human; C583889:ALG13 protein, human