A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation.
Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Patrick S
PS
Tarpey
Raffaella
R
Smith
Erin
E
Pleasance
Annabel
A
Whibley
Sarah
S
Edkins
Claire
C
Hardy
Sarah
S
O'Meara
Calli
C
Latimer
Ed
E
Dicks
Andrew
A
Menzies
Phil
P
Stephens
Matt
M
Blow
Chris
C
Greenman
Yali
Y
Xue
Chris
C
Tyler-Smith
Deborah
D
Thompson
Kristian
K
Gray
Jenny
J
Andrews
Syd
S
Barthorpe
Gemma
G
Buck
Jennifer
J
Cole
Rebecca
R
Dunmore
David
D
Jones
Mark
M
Maddison
Tatiana
T
Mironenko
Rachel
R
Turner
Kelly
K
Turrell
Jennifer
J
Varian
Sofie
S
West
Sara
S
Widaa
Paul
P
Wray
Jon
J
Teague
Adam
A
Butler
Andrew
A
Jenkinson
Mingming
M
Jia
David
D
Richardson
Rebecca
R
Shepherd
Richard
R
Wooster
M Isabel
MI
Tejada
Francisco
F
Martinez
Gemma
G
Carvill
Rene
R
Goliath
Arjan P M
AP
de Brouwer
Hans
H
van Bokhoven
Hilde
H
Van Esch
Jamel
J
Chelly
Martine
M
Raynaud
Hans-Hilger
HH
Ropers
Fatima E
FE
Abidi
Anand K
AK
Srivastava
James
J
Cox
Ying
Y
Luo
Uma
U
Mallya
Jenny
J
Moon
Josef
J
Parnau
Shehla
S
Mohammed
John L
JL
Tolmie
Cheryl
C
Shoubridge
Mark
M
Corbett
Alison
A
Gardner
Eric
E
Haan
Sinitdhorn
S
Rujirabanjerd
Marie
M
Shaw
Lucianne
L
Vandeleur
Tod
T
Fullston
Douglas F
DF
Easton
Jackie
J
Boyle
Michael
M
Partington
Anna
A
Hackett
Michael
M
Field
Cindy
C
Skinner
Roger E
RE
Stevenson
Martin
M
Bobrow
Gillian
G
Turner
Charles E
CE
Schwartz
Jozef
J
Gecz
F Lucy
FL
Raymond
P Andrew
PA
Futreal
Michael R
MR
Stratton
D002874:Chromosome Mapping; D041321:Chromosomes, Human, X / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*