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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
Nature. 2012 May 10; 485(7397):246-50
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09 May 2012
Genevieve Konopka
F1000 Neurological Disorders
University of Texas Southwestern Medical Center,
Dallas, TX, USA.
F1000 Neurological Disorders
University of Texas Southwestern Medical Center,
Dallas, TX, USA.
New Finding
DOI: 10.3410/f.716397823.790202800
The authors of this paper, similar to two other papers in the same issue of Nature {1,2}, have conducted exome sequencing of patients with autism spectrum disorders (ASDs) and unaffected family members. These studies identified mutations in several new genes for ASD as well as biological pathways that...Continue reading
The authors of this paper, similar to two other papers in the same issue of Nature {1,2}, have conducted exome sequencing of patients with autism spectrum disorders (ASDs) and unaffected family members. These studies identified mutations in several new genes for ASD as well as biological pathways that are important in the disorder. In addition, the authors have found an increase in risk for ASD with increasing paternal age. Together, these studies predict that up to 800 genetic loci may be responsible for the complex genetic architecture of ASD.
References
1.
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
Nature 2012 Apr 4
PMID: 22495306
DOI: 10.1038/nature10945
2.
Patterns and rates of exonic de novo mutations in autism spectrum disorders.
Nature 2012 Apr 4
PMID: 22495311
DOI: 10.1038/nature11011
Disclosures
None declared
Add Comment
Konopka G: F1000Prime Recommendation of [O'Roak BJ et al., Nature 2012, 485(7397):246-50]. In F1000Prime, 09 May 2012; DOI: 10.3410/f.716397823.790202800. F1000Prime.com/716397823#eval790202800
24 May 2012
Confirmation, New Finding, Technical Advance
DOI: 10.3410/f.716397823.791302874
This article is one of three published back-to-back (see also {1,2} and my F1000 evaluation of the latter {3}) that use exome sequencing to identify de novo likely pathogenic mutations in individuals with sporadic idiopathic autism.
These authors studied 189 new trios of an affected child and both...Continue reading
These authors studied 189 new trios of an affected child and both...Continue reading
This article is one of three published back-to-back (see also {1,2} and my F1000 evaluation of the latter {3}) that use exome sequencing to identify de novo likely pathogenic mutations in individuals with sporadic idiopathic autism.
These authors studied 189 new trios of an affected child and both parents from the Simons Simplex Collection, as well as 20 trios reported previously in which they identified four potentially pathogenic de novo mutations {4}. The authors validated >200 de novo events, of which 120 were felt to be severe; 28% of these produced a truncated protein. Recurrent de novo events were found in 2 genes – CHD8 and NTNG1. In addition, the authors demonstrated a 4:1 paternal bias for the de novo events and a positive correlation with increasing paternal age. Some of the genes identified overlap with the other two reports, and methods were similar among all three groups. In sum, these papers confirm and extend the extreme locus heterogeneity and complexity of gene identification in autism spectrum disorders.
These authors studied 189 new trios of an affected child and both parents from the Simons Simplex Collection, as well as 20 trios reported previously in which they identified four potentially pathogenic de novo mutations {4}. The authors validated >200 de novo events, of which 120 were felt to be severe; 28% of these produced a truncated protein. Recurrent de novo events were found in 2 genes – CHD8 and NTNG1. In addition, the authors demonstrated a 4:1 paternal bias for the de novo events and a positive correlation with increasing paternal age. Some of the genes identified overlap with the other two reports, and methods were similar among all three groups. In sum, these papers confirm and extend the extreme locus heterogeneity and complexity of gene identification in autism spectrum disorders.
References
1.
Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.
Nat Genet 2011 Jun; 43(6): 585-9
PMID: 21572417
DOI: 10.1038/ng.835
2.
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
Nature 2012 May 10; 485(7397): 237-41
PMID: 22495306
DOI: 10.1038/nature10945
3.
Herman G: 'This article is one of three published back-to-back (see also {1,2} and my...' of: (Sanders SJ et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012 May 10; 485(7397):237-41; doi: 10.1038/nature10945). Faculty of 1000, 24 May 2012. F1000 evaluation
4.
Patterns and rates of exonic de novo mutations in autism spectrum disorders.
Nature 2012 May 10; 485(7397): 242-5
PMID: 22495311
DOI: 10.1038/nature11011
Disclosures
None declared
Herman G: F1000Prime Recommendation of [O'Roak BJ et al., Nature 2012, 485(7397):246-50]. In F1000Prime, 24 May 2012; DOI: 10.3410/f.716397823.791302874. F1000Prime.com/716397823#eval791302874
F1000Prime Recommendations, Dissents and Comments for [O'Roak BJ et al., Nature 2012, 485(7397):246-50]. In F1000Prime, 22 May 2013; F1000Prime.com/716397823
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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 β-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.
DOI: 10.1038/nature10989
PMID: 22495309
