Strong association of de novo copy number mutations with autism.

TitleStrong association of de novo copy number mutations with autism.
Publication TypeJournal Article
Year of Publication2007
AuthorsSebat, J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee Y-H, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King M-C, Skuse D, Geschwind DH, Gilliam CT, Ye K, Wigler M
JournalScience (New York, N.Y.)
Volume316
Issue5823
Pagination445-9
Date Published2007 Apr 20
ISSN1095-9203
KeywordsAsperger Syndrome, Autistic Disorder, Case-Control Studies, Child, Cytogenetic Analysis, Female, Gene Deletion, Gene Dosage, Gene Duplication, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Humans, In Situ Hybridization, Fluorescence, Male, Markov Chains, Microsatellite Repeats, Mutation, Nucleic Acid Hybridization, Oligonucleotide Array Sequence Analysis, Parents, Siblings
Abstract

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.

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