title: Structural variation of chromosomes in autism spectrum disorder.
abstract: Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Abdul
authors.initials: A
authors.lastname: Noor
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
authors.forename: Jennifer
authors.initials: J
authors.lastname: Skaug
authors.forename: Mary
authors.initials: M
authors.lastname: Shago
authors.forename: Rainald
authors.initials: R
authors.lastname: Moessner
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.forename: Bhooma
authors.initials: B
authors.lastname: Thiruvahindrapduram
authors.forename: Andreas
authors.initials: A
authors.lastname: Fiebig
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Jan
authors.initials: J
authors.lastname: Friedman
authors.forename: Cees E J
authors.initials: CE
authors.lastname: Ketelaars
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.forename: Can
authors.initials: C
authors.lastname: Ficicioglu
authors.forename: Susan
authors.initials: S
authors.lastname: Kirkpatrick
authors.forename: Rob
authors.initials: R
authors.lastname: Nicolson
authors.forename: Leon
authors.initials: L
authors.lastname: Sloman
authors.forename: Anne
authors.initials: A
authors.lastname: Summers
authors.forename: Clare A
authors.initials: CA
authors.lastname: Gibbons
authors.forename: Ahmad
authors.initials: A
authors.lastname: Teebi
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Ann
authors.initials: A
authors.lastname: Thompson
authors.forename: Cathy
authors.initials: C
authors.lastname: Vardy
authors.forename: Vicki
authors.initials: V
authors.lastname: Crosbie
authors.forename: Sandra
authors.initials: S
authors.lastname: Luscombe
authors.forename: Rebecca
authors.initials: R
authors.lastname: Baatjes
authors.forename: Lonnie
authors.initials: L
authors.lastname: Zwaigenbaum
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.forename: Bridget
authors.initials: B
authors.lastname: Fernandez
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002869:Chromosome Aberrations; D018628:Gene Dosage / Q000235:genetics*; D015321:Gene Rearrangement / Q000235:genetics; D005826:Genetics, Medical / Q000379:methods; D006801:Humans; D007621:Karyotyping; D046228:Microarray Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics