1. Structural variation of chromosomes in autism spectrum disorder
- Author
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Anath C. Lionel, Clare A. Gibbons, Jan M. Friedman, David Chitayat, Leon Sloman, Rebecca Baatjes, Andreas Fiebig, Lars Feuk, Christian R. Marshall, John B. Vincent, Mary Shago, Rob Nicolson, Rosanna Weksberg, Lonnie Zwaigenbaum, Sandra Luscombe, Peter Szatmari, Yvonne J. Vos, Can Ficicioglu, Anne Summers, Stephen W. Scherer, Bhooma Thiruvahindrapduram, Ahmad S. Teebi, Abdul Noor, Ann Thompson, Yan Ren, Stefan Schreiber, Bridget A. Fernandez, Rainald Moessner, Dalila Pinto, Susan J. Kirkpatrick, Vicki Crosbie, Jennifer Skaug, Cathy Vardy, Cees E.J. Ketelaars, Wendy Roberts, and Faculteit Medische Wetenschappen/UMCG
- Subjects
CNTNAP2 ,MICRODELETION SYNDROME ,NUCLEOTIDE ,Genetics, Medical ,Population ,Gene Dosage ,Epigenetics of autism ,Biology ,Polymorphism, Single Nucleotide ,Article ,Structural variation ,mental disorders ,Genetics ,Humans ,Heritability of autism ,Genetics(clinical) ,Copy-number variation ,Autistic Disorder ,education ,Genetics (clinical) ,POPULATION ,COPY NUMBER VARIATION ,Chromosome Aberrations ,Gene Rearrangement ,education.field_of_study ,HIGH-FREQUENCY ,GENETIC DISORDER ,MUTATIONS ,REARRANGEMENTS ,Gene rearrangement ,Microdeletion syndrome ,Microarray Analysis ,ARRAYS ,GENOME ,Phenotype ,Karyotyping - 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.
- Published
- 2007