title: Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families.
abstract: Rare mutations, including copy-number variants (CNVs), contribute significantly to autism spectrum disorder (ASD) risk. Although their importance has been established in families with only one affected child (simplex families), the contribution of both de novo and inherited CNVs to ASD in families with multiple affected individuals (multiplex families) is less well understood. We analyzed 1,532 families from the Autism Genetic Resource Exchange (AGRE) to assess the impact of de novo and rare CNVs on ASD risk in multiplex families. We observed a higher burden of large, rare CNVs, including inherited events, in individuals with ASD than in their unaffected siblings (odds ratio [OR] = 1.7), but the rate of de novo events was significantly lower than in simplex families. In previously characterized ASD risk loci, we identified 49 CNVs, comprising 24 inherited events, 19 de novo events, and 6 events of unknown inheritance, a significant enrichment in affected versus control individuals (OR = 3.3). In 21 of the 30 families (71%) in whom at least one affected sibling harbored an established ASD major risk CNV, including five families harboring inherited CNVs, the CNV was not shared by all affected siblings, indicating that other risk factors are contributing. We also identified a rare risk locus for ASD and language delay at chromosomal region 2q24 (implicating NR4A2) and another lower-penetrance locus involving inherited deletions and duplications of WWOX. The genetic architecture in multiplex families differs from that in simplex families and is complex, warranting more complete genetic characterization of larger multiplex ASD cohorts.
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors: Virpi M
authors: VM
authors: Leppa
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Stephanie N
authors: SN
authors: Kravitz
authors: Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA 18704, USA.
authors: Christa Lese
authors: CL
authors: Martin
authors: Institut de Génétique Médicale, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire de Lille, Lille 59037, France.
authors: Joris
authors: J
authors: Andrieux
authors: Service de Génétique Medicale, Centre Hospitalier Universitaire Nantes, 9 Quai Moncousu, Nantes 44093, France; Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, INSERM UMR-957, Nantes 44000, France.
authors: Cedric
authors: C
authors: Le Caignec
authors: Service de Génétique, Centre Hospitalier Le Mans, 194 Avenue Rubillard, Le Mans 72037, France.
authors: Dominique
authors: D
authors: Martin-Coignard
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Christina
authors: C
authors: DyBuncio
authors: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Stephan J
authors: SJ
authors: Sanders
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA.
authors: Jennifer K
authors: JK
authors: Lowe
authors: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Rita M
authors: RM
authors: Cantor
authors: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Center for Autism Research and Treatment and Program in Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.
authors: Daniel H
authors: DH
authors: Geschwind
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D030541:Databases, Genetic; D005091:Exons / Q000235:genetics; D005260:Female; D020440:Gene Duplication / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007805:Language Development Disorders / Q000235:genetics; D008297:Male; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010088:Oxidoreductases / Q000235:genetics; D019683:Penetrance; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D017384:Sequence Deletion / Q000235:genetics; D035781:Siblings; D025521:Tumor Suppressor Proteins / Q000235:genetics; D020506:Untranslated Regions / Q000235:genetics; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D025521:Tumor Suppressor Proteins; D020506:Untranslated Regions; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human