Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability.
Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.
Noor
Abdul
A
Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Whibley
Annabel
A
Marshall
Christian R
CR
Gianakopoulos
Peter J
PJ
Piton
Amelie
A
Carson
Andrew R
AR
Orlic-Milacic
Marija
M
Lionel
Anath C
AC
Sato
Daisuke
D
Pinto
Dalila
D
Drmic
Irene
I
Noakes
Carolyn
C
Senman
Lili
L
Zhang
Xiaoyun
X
Mo
Rong
R
Gauthier
Julie
J
Crosbie
Jennifer
J
Pagnamenta
Alistair T
AT
Munson
Jeffrey
J
Estes
Annette M
AM
Fiebig
Andreas
A
Franke
Andre
A
Schreiber
Stefan
S
Stewart
Alexandre F R
AF
Roberts
Robert
R
McPherson
Ruth
R
Guter
Stephen J
SJ
Cook
Edwin H
EH
Dawson
Geraldine
G
Schellenberg
Gerard D
GD
Battaglia
Agatino
A
Maestrini
Elena
E
Jeng
Linda
L
Hutchison
Terry
T
Rajcan-Separovic
Evica
E
Chudley
Albert E
AE
Lewis
Suzanne M E
SM
Liu
Xudong
X
Holden
Jeanette J
JJ
Fernandez
Bridget
B
Zwaigenbaum
Lonnie
L
Bryson
Susan E
SE
Roberts
Wendy
W
Szatmari
Peter
P
Gallagher
Louise
L
Stratton
Michael R
MR
Gecz
Jozef
J
Brady
Angela F
AF
Schwartz
Charles E
CE
Schachar
Russell J
RJ
Monaco
Anthony P
AP
Rouleau
Guy A
GA
Hui
Chi-Chung
CC
Lucy Raymond
F
F
Scherer
Stephen W
SW
Vincent
John B
JB
D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015221:Potassium Channels / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases