title: Transmission disequilibrium of small CNVs in simplex autism.
abstract: We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.004; odds ratio [OR] = 1.19) and that the probands' CNVs affected more genes (921 versus 726, p = 0.02; OR = 1.30). These smaller CNVs (median size 18 kb) were transmitted preferentially from the mother (136 maternal versus 100 paternal, p = 0.02), although this bias occurred irrespective of affected status. The excess burden of inherited CNVs among probands was driven primarily by sibling pairs with discordant social-behavior phenotypes (p < 0.0002, measured by Social Responsiveness Scale [SRS] score), which contrasts with families where the phenotypes were more closely matched or less extreme (p > 0.5). Finally, we found enrichment of brain-expressed genes unique to probands, especially in the SRS-discordant group (p = 0.0035). In a combined model, our inherited CNVs, de novo CNVs, and de novo single-nucleotide variants all independently contributed to the risk of autism (p < 0.05). Taken together, these results suggest that small transmitted rare CNVs play a role in the etiology of simplex autism. Importantly, the small size of these variants aids in the identification of specific genes as additional risk factors associated with ASD.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.forename: Emre
authors.initials: E
authors.lastname: Karakoc
authors.forename: Kiana
authors.initials: K
authors.lastname: Mohajeri
authors.forename: Ben
authors.initials: B
authors.lastname: Nelson
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Jeff
authors.initials: J
authors.lastname: Munson
authors.forename: Raphe
authors.initials: R
authors.lastname: Bernier
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012307:Risk Factors; D035781:Siblings
references.citation: Nature. 2012 Apr 04;485(7397):246-50
references.pmid: 22495309
references.citation: Nature. 2012 Apr 04;485(7397):242-5
references.pmid: 22495311
references.citation: Neuron. 2010 Jun 10;66(5):768-80
references.pmid: 20547133
references.citation: N Engl J Med. 2012 Oct 4;367(14):1321-31
references.pmid: 22970919
references.citation: Nature. 2010 Jul 15;466(7304):368-72
references.pmid: 20531469
references.citation: J Med Genet. 2011 Nov;48(11):776-8
references.pmid: 21969336
references.citation: Am J Med Genet A. 2012 Aug;158A(8):1962-6
references.pmid: 22488736
references.citation: FEBS J. 2012 Dec;279(23):4398-409
references.pmid: 23061666
references.citation: Ann Hum Genet. 2007 Sep;71(Pt 5):570-7
references.pmid: 17451405
references.citation: Glia. 2012 Aug;60(8):1203-14
references.pmid: 22378467
references.citation: Nat Genet. 1999 Sep;23(1):47-51
references.pmid: 10471497
references.citation: Nat Methods. 2010 Aug;7(8):576-7
references.pmid: 20676076
references.citation: Nature. 2009 May 28;459(7246):569-73
references.pmid: 19404257
references.citation: Neuron. 2010 Oct 21;68(2):192-5
references.pmid: 20955926
references.citation: Neuron. 2011 Jun 9;70(5):863-85
references.pmid: 21658581
references.citation: BMC Genomics. 2010 Mar 26;11:206
references.pmid: 20346131
references.citation: Neuron. 2011 Jun 9;70(5):886-97
references.pmid: 21658582
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
references.pmid: 15075390
references.citation: Am J Hum Genet. 2012 Dec 7;91(6):1073-81
references.pmid: 23176823
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Jun 5;147B(4):424-33
references.pmid: 17948871
references.citation: Arch Gen Psychiatry. 2011 Nov;68(11):1095-102
references.pmid: 21727249
references.citation: G3 (Bethesda). 2012 Dec;2(12):1665-85
references.pmid: 23275889
references.citation: Mol Psychiatry. 2013 Feb;18(2):137-8
references.pmid: 22371046
references.citation: PLoS Biol. 2009 Feb 24;7(2):e41
references.pmid: 19243221
references.citation: Genome Res. 2012 Aug;22(8):1525-32
references.pmid: 22585873
references.citation: Nat Genet. 2011 Jun;43(6):585-9
references.pmid: 21572417
references.citation: J Cell Biol. 2005 Aug 15;170(4):527-35
references.pmid: 16087709
references.citation: Neuron. 2012 Apr 26;74(2):285-99
references.pmid: 22542183
references.citation: Nature. 2012 Apr 04;485(7397):237-41
references.pmid: 22495306
references.citation: J Autism Dev Disord. 2014 Oct;44(10):2392-9
references.pmid: 22382605
references.citation: Science. 2007 Apr 20;316(5823):445-9
references.pmid: 17363630
references.citation: Bioinformatics. 2007 Mar 15;23(6):657-63
references.pmid: 17234643
references.citation: Psychol Med. 1995 Jan;25(1):63-77
references.pmid: 7792363