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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
Open accessAbstract
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.
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In the citing paper
“Exome sequencing of ASD/ID families has revealed a significant excess of de novo mutations in probands when compared to unaffected siblings and has identified novel candidate genes contributing to the neurological deficits.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [24]
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In the citing paper
“including that, prima facie , most proteins encoded by ASD risk genes are involved either in synaptic structure and function or chromatin modification and regulation of gene expression 38,46,47,58 (Fig. 3).”
From Autism spectrum disorder (2020) · cites this paper as [38]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Various genetic approaches have been successful in identifying the causes of more than 1,000 Mendelian, and fewer non-Mendelian, forms of neurodevelopmental disorders: prototypical examples are intellectual disability62–68, autism spectrum disorder (ASD)69–77, epilepsy78,79 and schizophrenia80–82.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [71]
In the citing paper
“CNVs and SNPs have both been reported to play a major role in autism incidence (36–41).”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [39]
In the citing paper
“An analysis of publicly released whole exome sequence data (Iossifov et al., 2012; O’Roak et al., 2012; Sanders et al., 2012) showed a modest trend towards an excess of biallelic, inherited, rare (MAF<1%), protein-altering variants in cases (8/612 ) compared to control siblings (2/419) (p=0.21, Fisher’s exact test, two-tailed) in at least one of the genes we screened (Table S5).”
From Using Whole-Exome Sequencing to Identify Inherited Causes of Autism (2013) · cites this paper as O’Roak et al., 2012
In the citing paper
“Hypomorphic, biallelic mutations, combined with CNVs and heterozygous stop mutations (Neale et al., 2012; O’Roak et al., 2012; Sanders et al., 2012) which completely inactivate one of two alleles, suggest that a common theme for ASD mutations in general might be partial loss of gene function and/or dosage sensitivity.”
From Using Whole-Exome Sequencing to Identify Inherited Causes of Autism (2013) · cites this paper as O’Roak et al., 2012
In the citing paper
“Together, results from these papers demonstrate a significant role for rare SNVs in genetic liability for ASD”
From Sex differences in autism spectrum disorders (2013) · cites this paper as [49]
In the citing paper
“Exome and whole-genome sequencing studies have estimated at least another ∼6% contribution to ASD7–10,15”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [10]
In the citing paper
“and three other recent studies by Sanders et al.8, O’Roak et al.7 and Neale et al.23 (65 genes combined from all three; referred to as ‘SON-exomes’);”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [7]
In the citing paper
“Genetic investigations in ASD have constructed seed-based networks with literature-curated PPIs to identify the convergence of ASD risk genes71,73.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [71]
In the citing paper
“This approach was applied to identify a highly interconnected PPI subnetwork among rare de novo variants in ASD71.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [71]
In the citing paper
“Many strong neurobiological candidates have emerged from the genes disrupted by de novo mutations in these studies, including mutations in previously identified ASD/ID genes.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [24]
In the citing paper
“We note that the strongest effects are observed for de novo loss-of-function (or truncating) mutations”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [24]
In the citing paper
“New exome sequencing technology has identified novel rare variants and has found that sporadic cases of ASD/ID are enriched for disruptive de novo mutations.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [24]
In the citing paper
“Another striking candidate is DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A), for which three truncating mutations have been discovered in autism probands [24,44] and de novo structural variants in ID probands [54,55].”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [24]
In the citing paper
“In summary, only three genes [CHD8, SCN2A, and synaptic Ras GTPase activating protein 1 (SYNGAP1)] had two independent truncating de novo mutations in any single study, and no gene had more than three mutations.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [24]
In the citing paper
“one de novo frameshift of ARID1B was found in a sporadic ASD case [24]”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [24]
In the citing paper
“In the case of paternal age, one mediating mechanism lies in the increased rate of de novo SNV and CNV with advancing paternal age (22,24,25,43,44).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [25]
In the citing paper
“TBR1 has been implicated in ASD (21,22,25,26) and ID (73).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [25]
In the citing paper
“Qualitatively, recent studies of rare variants also find it challenging to distinguish risk variation from the background stochastic noise (12–15).”
From Individual common variants exert weak effects on the risk for autism spectrum disorders (2012) · cites this paper as [13]
In the citing paper
“De novo loss of function mutations in this gene had previously been identified in two patients by WES2 and targeted resequencing16 of patients with ASD. In those studies however, causal relationship did not reach locus-specific significance.”
From A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP (2014) · cites this paper as [2]
In the citing paper
“Albeit rare, de novo mutations have emerged as substantial contributors to ASD risk [83, 165, 166, 254, 261, 309].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [261]
In the citing paper
“Chromodomain helicase DNA-binding protein 8 (CHD8), encoding a chromatin modifying gene on chromosome 14q11.2, is one of the high-penetrance ASD risk genes recently identified by sequencing studies [83, 165, 261, 347].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [261]
In the citing paper
“no truncating coding-sequence variation within SHANK1 and SHANK3”
From Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments (2014) · cites this paper as [36]
In the citing paper
“Recent exome sequencing studies only reported one de novo SHANK2 mutation out of 965 patients [32], [36], [37]”
From Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments (2014) · cites this paper as [36]
In the citing paper
“estimates from de novo exonic mutations (similar to those from SV data) suggest that ASD is highly polygenic (estimates ranged from 400–1000 genes). 84,85”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [85]
In the citing paper
“Three recent papers describe the results from exome sequencing of ~600 trios, and identify roles for de novo exonic mutations in SCN2A, KATNAL2, and CHD8 in the pathogenesis of ASD. 83–85”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [85]
In the citing paper
“Intriguingly, all three studies noted an increased rate of de novo exonic mutations in older parents (with the mutations generally being of paternal origin), 83–85”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [85]
In the citing paper
“However, a central finding from these papers was that only a minority of cases had a de novo putatively functional variant”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [85]
In the citing paper
“Unexpectedly, simplex and multiplex ASD pedigrees show relatively similar de novo mutation rates for SV 80,81 and exonic variation. 83–85”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [85]
In the citing paper
“Projections for ASD and SCZ suggest that variation at hundreds of different genes will ultimately be shown to be involved. 58,80,85”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [85]
In the citing paper
“The published results for ASD 83–85 and unpublished data on SCZ suggest these issues will be important and underscore the need for sequencing studies to have the same emphasis on statistical rigor and large sample sizes that has enabled GWAS to realize success for multiple psychiatric disorders. 154”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [85]
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“Previous studies have demonstrated evidence of a strong association of ASD, SCZ, BD, and ID with the following 11 CNV loci (deletions and/or duplications): 1q21.”
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“Advances in this area have led to identification and discovery of many new de novomutations in ASD [16,153,204].”
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BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription
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The shape of the human language-ready brain
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The origins, determinants, and consequences of human mutations
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Self-citationThe development of autism spectrum disorders: variability and causal complexity
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“For older fathers, the increase in risk is slightly greater,(40) in part because spontaneous genetic mutations are predominantly paternal in origin.(41) Complications of pregnancy, including gestational diabetes and gestational bleeding have been linked to increased ASD risk, as has maternal exposure to certain chemic…”
Human induced pluripotent stem cells for modelling neurodevelopmental disorders
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The Emerging Clinical Neuroscience of Autism Spectrum Disorder
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Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders
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Self-citationMolecular and network-level mechanisms explaining individual differences in autism spectrum disorder
Buch, A. M., Vértes, P. E., Seidlitz, J., Kim, S. H., Grosenick, L., & Liston, C. M. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01259-x · Cited by 163
Genomic Perspectives of Transcriptional Regulation in Forebrain Development
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“Evidence is mounting for dosage effects or haploinsufficiency of developmental TFs, such as TBR1, and chromatin remodeling proteins, such as CHD8, as a mechanism in these disorders (O’Roak et al., 2011, 2012a, 2012b).”
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Autism Risk Across Generations
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Brain connectivity in autism spectrum disorder
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Genetics of structural and functional brain changes in autism spectrum disorder
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“They apply their particular tolerance score on targets from a subset of the Simons Simplex Collection (SSC), a collection of simplex autism families (5, 7, 8, 15).”
BackgroundThe role of AUTS2 in neurodevelopment and human evolution
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Neocortical neurogenesis and the etiology of autism spectrum disorder
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Rescue of oxytocin response and social behaviour in a mouse model of autism
Hörnberg, H., Pérez-Garci, E., Schreiner, D., Hatstatt-Burklé, L., Magara, F., Baudouin, S., Matter, A., Nacro, K., Pecho-Vrieseling, E., & Scheiffele, P. (2020) · Nature · doi:10.1038/s41586-020-2563-7 · Cited by 154
Novel genetic causes for cerebral visual impairment
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Major channels involved in neuropsychiatric disorders and therapeutic perspectives
Imbrici, P., Camerino, D. C., & Tricarico, D. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00076 · Cited by 151
“…by ion channels in psychiatric disorders (Gargus, 2006, 2009; Liao and Soong, 2010; Sicca et al., 2011; Askland et al., 2012; Mele et al., 2012; O’Roak et al., 2012) and their specific function and localization in brain areas implicated in mental illness (Hibino et al., 2010; Catterall, 2012;…”
BackgroundInfluentialFeinberg, J. I., Bakulski, K. M., Jaffe, A. E., Tryggvadóttir, R., Brown, S. C., Goldman, L. R., Croen, L., Hertz‐Picciotto, I., Newschaffer, C. J., Fallin, M. D., et al. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv028 · Cited by 155
Distinct roles of GRIN2A and GRIN2B variants in neurological conditions
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Autism spectrum disorders: from genes to neurobiology
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“However, more recent exome sequencing studies have now confirmed that de novo coding single nucleotide variants (SNVs) and de novo insertion deletions (indels) similarly contribute substantial risk for ASD [31,32 ,33,34 , 35 ,36,38 ,39 ].”
BackgroundMethodInfluentialThe role of BAF (mSWI/SNF) complexes in mammalian neural development
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“The role of nBAF in the adult CNS may be the basis for the pathogenicity of BAF subunit mutations in psychiatric disorders [Koga et al., 2009; Loe‐Mie et al., 2010; Nord et al., 2011; Neale et al., 2012; O’Roak et al., 2012].”
BackgroundInfluentialThe Cancer Cell Map Initiative: Defining the Hallmark Networks of Cancer
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“A number of studies have recently demonstrated the power of network-guided GWAS for diverse diseases such as autism (O’Roak et al., 2012; Parikshak et al., 2013; Willsey et al., 2013), multiple sclerosis (Baranzini et al.”
BackgroundFeng, W., Khan, M. A., Bellvís, P., Zhu, Z., Bernhardt, O., Herold‐Mende, C. C., & Liu, H. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.05.002 · Cited by 154
“, 2010), were recently identified as one of the major genetic lesions in human autism patients (Neale et al., 2012; O’Roak et al., 2012; Talkowski et al., 2012).”
A quarter century of progress on the early detection and treatment of autism spectrum disorder
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Self-citationExome sequencing to identify de novo mutations in sporadic ALS trios
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Prioritization of neurodevelopmental disease genes by discovery of new mutations
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Self-citationJi, J., Lee, H., Argiropoulos, B., Dorrani, N., Mann, J., Martinez-Agosto, J. A., Gomez-Ospina, N., Gallant, N., Bernstein, J. A., Hudgins, L., et al. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2015.71 · Cited by 145
Autism-Associated Promoter Variant in MET Impacts Functional and Structural Brain Networks
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“…the vast majority of evidence comes from rare mutations, such as the recently described copy number variants (CNVs) (Marshall et al., 2008; Pinto et al., 2010) and de novo single-nucleotide variants (SNVs) (Sanders et al., 2012; O’Roak et al., 2012; Neale et al., 2012; Iossifov et al., 2012).”
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Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features
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“This underlines the recent proposal that the β -catenin protein–interacting network is important in abnormal neurodevelopmental etiology (12, 25).”
InfluentialLage, K., Greenway, S. C., Rosenfeld, J. A., Wakimoto, H., Gorham, J., Segrè, A. V., Roberts, A. E., Smoot, L. B., Pu, W. T., Pereira, A. C., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1210730109 · Cited by 148
“For example, pairs of CNVs within a genome convey greater risk for severe developmental delay than individual CNVs (23), and de novo exon mutations in autism patients physically interact in protein interaction networks (19, 20).”
BackgroundGenetics and epigenetics of autism: A Review
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“, in a Japanese study genotyping 243 patients and 667 controls),(46) and these mutations may be part of a highly interconnected protein network related to brain development.(47)”
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“CHD7 variants have been reported in individuals with isolated features including Autism Spectrum Disorder [O’Roak et al., 2012; Jiang et al., 2013] or gonadotropin-releasing hormone deficiency [Balasubramanian et al., 2014], but not cardiac defects [Corsten-Janssen et al., 2014] or cleft palate…”
BackgroundAutism Spectrum Disorder Genetics and the Search for Pathological Mechanisms
Manoli, D. S., & State, M. W. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20111608 · Cited by 159
New and emerging approaches to treat psychiatric disorders
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Autism Spectrum Disorder and Epilepsy
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An adaptationist perspective on the etiology of depression
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Dravet syndrome: a sodium channel interneuronopathy
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Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
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“Although the overall rate of DNM, in general, does not differ between affected and unaffected siblings, patients with NDDs show an enrichment for LGD and missense DNMs [8, 10, 12, 13, 79].”
BackgroundMethodInfluentialSelf-citation
Metadata
- Authors
- O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., Turner, E. H., Stanaway, I. B., Vernot, B., Malig, M., Baker, C., Reilly, B., Akey, J. M., Borenstein, E., Rieder, M. J., Nickerson, D. A., Bernier, R., Shendure, J., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Santa Fe Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shendure, Jay
- Eichler, Evan E.
- ORCID
- Venue
- Nature
- Published
- 2012-04-04
- Volume
- 485
- Issue
- 7397
- Pages
- 246-250
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3350576
- OpenAlex
- W1964444099
- Cited by
- 2,165
- References
- 50
- Citations by year
- 2026: 42 · 2025: 68 · 2024: 85 · 2023: 101 · 2022: 104 · 2021: 137 · 2020: 151 · 2019: 147 · 2018: 143 · 2017: 173 · 2016: 198 · 2015: 219 · 2014: 262 · 2013: 212 · 2012: 118
- FWCI
- 131.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Simons Foundation
- University of Washington
- Simons Foundation Autism Research Initiative (137578)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-102924, RC2HL102926, RC2HL102923, UC2HL102924, HL 1029230, R01HL094976, HL094976, RC2HL102924, UC2HL102926, HL-102926)
- National Human Genome Research Institute
- National Institute of Environmental Health Sciences (HHSN273200800010C)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD065285, R01HD065285)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- de novo mutations, paternal age, protein-protein interaction network, β-catenin signaling, chromatin remodeling, CHD8, SCN2A, NTNG1, locus heterogeneity, simplex families, autism risk genes, parent-child trios, unaffected siblings, recurrent mutations, p53 pathway, copy number variation
- MeSH terms
- Netrins, Autistic Disorder, DNA-Binding Proteins, Exons, Humans, Laminin, Nerve Tissue Proteins, Parents, Stochastic Processes, Transcription Factors, Reproducibility of Results, Sodium Channels, Signal Transduction, Tumor Suppressor Protein p53, Receptors, N-Methyl-D-Aspartate, Point Mutation, Genetic Predisposition to Disease, Siblings, beta Catenin, GPI-Linked Proteins, Exome, Protein Interaction Maps, NAV1.1 Voltage-Gated Sodium Channel
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