Strong Association of De Novo Copy Number Mutations with Autism

• Published in: Science (American Association for the Advancement of Science) Vol. 316; no. 5823; pp. 445 - 449
• Main Authors: Sebat, Jonathan, Lakshmi, B, Malhotra, Dheeraj, Troge, Jennifer, Lese-Martin, Christa, Walsh, Tom, Yamrom, Boris, Yoon, Seungtai, Krasnitz, Alex, Kendall, Jude, Leotta, Anthony, Pai, Deepa, Zhang, Ray, Lee, Yoon-Ha, Hicks, James, Spence, Sarah J, Lee, Annette T, Puura, Kaija, Lehtimäki, Terho, Ledbetter, David, Gregersen, Peter K, Bregman, Joel, Sutcliffe, James S, Jobanputra, Vaidehi, Chung, Wendy, Warburton, Dorothy, King, Mary-Claire, Skuse, David, Geschwind, Daniel H, Gilliam, T. Conrad, Ye, Kenny, Wigler, Michael
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 20.04.2007; The American Association for the Advancement of Science
• Subjects: Asperger Syndrome - genetics; Autism; Autism Spectrum Disorders; Autistic disorder; Autistic Disorder - genetics; Biological and medical sciences; Case-Control Studies; Child; Child clinical studies; Comparative genomic hybridization; Cytogenetic Analysis; cytogenetics; Deoxyribonucleic acid; Developmental disorders; DNA; Female; Fluorescence in situ hybridization; Gene Deletion; Gene Dosage; Gene Duplication; Genes; Genetic markers; Genetic mutation; Genetic Predisposition to Disease; Genome, Human; Genomes; Genomics; genotyping; germ cells; Germ-Line Mutation; Human genetics; Humans; Hybridization; Hypothesis testing; In Situ Hybridization, Fluorescence; Infantile autism; Male; Markov Chains; Medical genetics; Medical sciences; Microsatellite Repeats; Mutation; Nucleic Acid Hybridization; Oligonucleotide Array Sequence Analysis; Parents; paternity; Patients; Pervasive child development disorders; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Risk factors; Siblings; Human; Autism; Family study; Copy number; Genetics; Developmental disorder; Mutation; Genetic determinism; Child; De novo
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1138659

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.