Publication Date:
2012-04-13
Description:
It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350576/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350576/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O'Roak, Brian J -- Vives, Laura -- Girirajan, Santhosh -- Karakoc, Emre -- Krumm, Niklas -- Coe, Bradley P -- Levy, Roie -- Ko, Arthur -- Lee, Choli -- Smith, Joshua D -- Turner, Emily H -- Stanaway, Ian B -- Vernot, Benjamin -- Malig, Maika -- Baker, Carl -- Reilly, Beau -- Akey, Joshua M -- Borenstein, Elhanan -- Rieder, Mark J -- Nickerson, Deborah A -- Bernier, Raphael -- Shendure, Jay -- Eichler, Evan E -- HD065285/HD/NICHD NIH HHS/ -- HHSN273200800010C/PHS HHS/ -- HL 094976/HL/NHLBI NIH HHS/ -- HL 1029230/HL/NHLBI NIH HHS/ -- HL 102924/HL/NHLBI NIH HHS/ -- HL102926/HL/NHLBI NIH HHS/ -- R01 HD065285/HD/NICHD NIH HHS/ -- R01 HD065285-02/HD/NICHD NIH HHS/ -- R01 HL094976/HL/NHLBI NIH HHS/ -- RC2 HL102923/HL/NHLBI NIH HHS/ -- RC2 HL102926/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Apr 4;485(7397):246-50. doi: 10.1038/nature10989.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495309" target="_blank"〉PubMed〈/a〉
Keywords:
Autistic Disorder/*genetics
;
DNA-Binding Proteins/genetics
;
Exome/*genetics
;
Exons/*genetics
;
GPI-Linked Proteins/genetics
;
Genetic Predisposition to Disease/genetics
;
Humans
;
Laminin/genetics
;
NAV1.1 Voltage-Gated Sodium Channel
;
Nerve Tissue Proteins/genetics
;
Parents
;
Point Mutation/*genetics
;
Protein Interaction Maps/*genetics
;
Receptors, N-Methyl-D-Aspartate/genetics
;
Reproducibility of Results
;
Siblings
;
Signal Transduction
;
Sodium Channels/genetics
;
Stochastic Processes
;
Transcription Factors/genetics
;
Tumor Suppressor Protein p53/metabolism
;
beta Catenin/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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