Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

By Brian J. O'Roak, Laura Vives, S. Girirajan, E. Karakoç, Niklas Krumm, Bradley P. Coe, Roie Levy, Arthur Ko, Choli Lee, Joshua D. Smith and 13 more. Nature, 2012

2,200 citations recorded by the source corpus.

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.

Subfields: Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/3e25910f8d57d593cccca521a59c52aa63c2dcc8

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Citations in the corpus

Whole Genome Sequencing in Autism Identifies Hotspots for De Novo Germline Mutation (2012, positive): “…correlated with mutation rate variation in a genome-wide data set from two trios (Conrad et al., 2011) (Figure 4B) and exome data sets from four independent trio-based studies of autism (Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2011, 2012; Sanders et al., 2012) (Figures 4C and 4D).”
The Next-Generation Sequencing Revolution and Its Impact on Genomics (2013, neutral): “Four large-scale studies (Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2012; Sanders et al., 2012) evaluated the impact of DNMs in autism spectrum disorder (ASD) via exome sequencing of family quartets (patient, parents, and an unaffected sibling).”
Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism (2013, neutral): “A. Jeremy Willsey,1,2 Stephan J. Sanders,1,2 Mingfeng Li,3,4 Shan Dong,1,5 Andrew T. Tebbenkamp,3,4 Rebecca A. Muhle,1,4,6 Steven K. Reilly,1 Leon Lin,7 Sofia Fertuzinhos,3,4 Jeremy A. Miller,8 Michael T. Murtha,9 Candace Bichsel,3,4 Wei Niu,1,4,6 Justin Cotney,1 A. Gulhan Ercan-Sencicek,6,9 Jake Go”
Scholarship, Research, and Creative Work at Bryn Mawr College Scholarship, Research, and Creative Work at Bryn Mawr College (background): “Realizing that context, intended as the sum of all the circumstances that may come into play around a work of art, could be in-definitely extended, it has argued that therefore total context is impossible to establish.”
A SPECTRAL APPROACH INTEGRATING FUNCTIONAL GENOMIC ANNOTATIONS FOR CODING AND NONCODING VARIANTS (2016, background): “In total for ASD, we have n = 2,027 such mutations among which 1, 753 are missense [22, 23, 24, 25, 26].”
News from the protein mutability landscape. (2013, background): “[6] O'RoakBJ, Vives L,GirirajanS, KarakocE, KrummN,CoeBP, et al.”
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci (2015, background): “…siblings across a wide range of mutation types, from copy number variants (CNVs) (Levy et al., 2011; Sanders et al., 2011), to small insertion/deletions (indels) (Dong et al., 2014), and single nucleotide variants (SNVs) (Iossifov et al., 2012, 2014; O’Roak et al., 2012; Sanders et al., 2012).”