Strong association of de novo copy number mutations with autism.
We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Sebat
Jonathan
J
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA. sebat@cshl.edu
Lakshmi
B
B
Malhotra
Dheeraj
D
Troge
Jennifer
J
Lese-Martin
Christa
C
Walsh
Tom
T
Yamrom
Boris
B
Yoon
Seungtai
S
Krasnitz
Alex
A
Kendall
Jude
J
Leotta
Anthony
A
Pai
Deepa
D
Zhang
Ray
R
Lee
Yoon-Ha
YH
Hicks
James
J
Spence
Sarah J
SJ
Lee
Annette T
AT
Puura
Kaija
K
Lehtimäki
Terho
T
Ledbetter
David
D
Gregersen
Peter K
PK
Bregman
Joel
J
Sutcliffe
James S
JS
Jobanputra
Vaidehi
V
Chung
Wendy
W
Warburton
Dorothy
D
King
Mary-Claire
MC
Skuse
David
D
Geschwind
Daniel H
DH
Gilliam
T Conrad
TC
Ye
Kenny
K
Wigler
Michael
M
D020817:Asperger Syndrome / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D020732:Cytogenetic Analysis; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008390:Markov Chains; D018895:Microsatellite Repeats; D009154:Mutation; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010290:Parents; D035781:Siblings