Structural variation of chromosomes in autism spectrum disorder.
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.
Marshall
Christian R
CR
The Centre for Applied Genomics, The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Noor
Abdul
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Vincent
John B
JB
Lionel
Anath C
AC
Feuk
Lars
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Skaug
Jennifer
J
Shago
Mary
M
Moessner
Rainald
R
Pinto
Dalila
D
Ren
Yan
Y
Thiruvahindrapduram
Bhooma
B
Fiebig
Andreas
A
Schreiber
Stefan
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Friedman
Jan
J
Ketelaars
Cees E J
CE
Vos
Yvonne J
YJ
Ficicioglu
Can
C
Kirkpatrick
Susan
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Nicolson
Rob
R
Sloman
Leon
L
Summers
Anne
A
Gibbons
Clare A
CA
Teebi
Ahmad
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Chitayat
David
D
Weksberg
Rosanna
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Thompson
Ann
A
Vardy
Cathy
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Crosbie
Vicki
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Luscombe
Sandra
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Baatjes
Rebecca
R
Zwaigenbaum
Lonnie
L
Roberts
Wendy
W
Fernandez
Bridget
B
Szatmari
Peter
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Scherer
Stephen W
SW
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