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.
Tarpey
Patrick S
PS
Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Smith
Raffaella
R
Pleasance
Erin
E
Whibley
Annabel
A
Edkins
Sarah
S
Hardy
Claire
C
O'Meara
Sarah
S
Latimer
Calli
C
Dicks
Ed
E
Menzies
Andrew
A
Stephens
Phil
P
Blow
Matt
M
Greenman
Chris
C
Xue
Yali
Y
Tyler-Smith
Chris
C
Thompson
Deborah
D
Gray
Kristian
K
Andrews
Jenny
J
Barthorpe
Syd
S
Buck
Gemma
G
Cole
Jennifer
J
Dunmore
Rebecca
R
Jones
David
D
Maddison
Mark
M
Mironenko
Tatiana
T
Turner
Rachel
R
Turrell
Kelly
K
Varian
Jennifer
J
West
Sofie
S
Widaa
Sara
S
Wray
Paul
P
Teague
Jon
J
Butler
Adam
A
Jenkinson
Andrew
A
Jia
Mingming
M
Richardson
David
D
Shepherd
Rebecca
R
Wooster
Richard
R
Tejada
M Isabel
MI
Martinez
Francisco
F
Carvill
Gemma
G
Goliath
Rene
R
de Brouwer
Arjan P M
AP
van Bokhoven
Hans
H
Van Esch
Hilde
H
Chelly
Jamel
J
Raynaud
Martine
M
Ropers
Hans-Hilger
HH
Abidi
Fatima E
FE
Srivastava
Anand K
AK
Cox
James
J
Luo
Ying
Y
Mallya
Uma
U
Moon
Jenny
J
Parnau
Josef
J
Mohammed
Shehla
S
Tolmie
John L
JL
Shoubridge
Cheryl
C
Corbett
Mark
M
Gardner
Alison
A
Haan
Eric
E
Rujirabanjerd
Sinitdhorn
S
Shaw
Marie
M
Vandeleur
Lucianne
L
Fullston
Tod
T
Easton
Douglas F
DF
Boyle
Jackie
J
Partington
Michael
M
Hackett
Anna
A
Field
Michael
M
Skinner
Cindy
C
Stevenson
Roger E
RE
Bobrow
Martin
M
Turner
Gillian
G
Schwartz
Charles E
CE
Gecz
Jozef
J
Raymond
F Lucy
FL
Futreal
P Andrew
PA
Stratton
Michael R
MR
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*