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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
“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 measuredIn 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
“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
“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
“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]
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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BackgroundChénier, S., Yoon, G., Argiropoulos, B., Lauzon, J. L., Laframboise, R., Ahn, J. W., Ogilvie, C. M., Lionel, A. C., Marshall, C. R., Vaags, A. K., et al. (2014) · Journal of Neurodevelopmental Disorders · doi:10.1186/1866-1955-6-9 · Cited by 99
“Analysis by aCGH in this 16-year-old girl was performed because of poorly controlled epilepsy as well as ASD.”
BackgroundInfluentialQuestions about DISC1 as a genetic risk factor for schizophrenia
Sullivan, P. F. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.182 · Cited by 93
Control of neural circuit formation by leucine-rich repeat proteins
de Wit, J., & Ghosh, A. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.07.004 · Cited by 97
Developmental maturation of astrocytes and pathogenesis of neurodevelopmental disorders
Yang, Y., Higashimori, H., & Morel, L. (2013) · Journal of Neurodevelopmental Disorders · doi:10.1186/1866-1955-5-22 · Cited by 99
“Although the exact causes for these disorders remain largely unknown, earlier genome-wide association studies (GWAS) [2-4] to recent exosome sequencing [5-8] have associated over 1,000 genes with various forms of neurodevelopmental disorders [9], including ASD, implicating a strong genetic component in their etiology.”
BackgroundWhole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder
Hashimoto, R., Nakazawa, T., Tsurusaki, Y., Yasuda, Y., Nagayasu, K., Matsumura, K., Kawashima, H., Yamamori, H., Fujimoto, M., Ohi, K., et al. (2015) · Journal of Human Genetics · doi:10.1038/jhg.2015.141 · Cited by 95
Ancien, F., Pucci, F., Godfroid, M., & Rooman, M. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-22531-2 · Cited by 91
“To analyze in more detail the performances of our predictors, we applied them to four different test sets S H , S NH , S CV and S SSC taken from 12 and specified in Tables S2– S5.”
MethodCoexpression networks identify brain region–specific enhancer RNAs in the human brain
Yao, P., Lin, P., Gokoolparsadh, A., Assareh, A. A., Thang, M. W. C., & Voineagu, I. (2015) · Nature Neuroscience · doi:10.1038/nn.4063 · Cited by 94
Exome Sequencing in 53 Sporadic Cases of Schizophrenia Identifies 18 Putative Candidate Genes
Guipponi, M., Santoni, F. A., Setola, V., Gehrig, C., Rothärmel, M., Cuenca, M., Guillin, O., Dikeos, D. G., Georgantopoulos, G., Papadimitriou, G. N., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0112745 · Cited by 92
“We did not observe a significant increase in the relative rate of loss-offunction-to-missense mutations in our cohort when compared to controls from published data sets [21, 22, 24, 26, 29, 30] (0.”
ResultJust, M. A., Cherkassky, V. L., Buchweitz, A., Keller, T. A., & Mitchell, T. M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113879 · Cited by 93
“The correlation with anatomy may be of particular interest because recent genomic research has uncovered several genetic alterations (copy number variants and single nucleotide variants) sometimes found in autism that are capable of altering axonal development and maintenance during early neurodevelopment, potentially…”
BackgroundThe Genetics of Autism Spectrum Disorders
Huguet, G., Benabou, M., & Bourgeron, T. (2016) · Research and perspectives in endocrine interactions · doi:10.1007/978-3-319-27069-2_11 · Cited by 105
Lalli, M. A., Avey, D. R., Dougherty, J. D., Milbrandt, J., & Mitra, R. D. (2020) · Genome Research · doi:10.1101/gr.262295.120 · Cited by 89
Sociability Deficits and Altered Amygdala Circuits in Mice Lacking Pcdh10, an Autism Associated Gene
Schoch, H., Kreibich, A. S., Ferri, S. L., White, R. S., Bohorquez, D., Banerjee, A., Port, R. G., Dow, H. C., Cordero, L., Pallathra, A. A., et al. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2016.06.008 · Cited by 92
“Human linkage studies have identified multiple ASD-associated genes that are implicated in the structure and function of neuronal synapses (4,8–10) including the cadherin and protocadherin superfamily of calcium-dependent neural cell adhesion molecules (9,11,12).”
BackgroundA Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons
Lin, Y., Frei, J. A., Kilander, M. B. C., Shen, W., & Blatt, G. J. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00263 · Cited by 97
Pagel, K. A., Pejaver, V. R., Lin, G. N., Nam, H.-J., Mort, M. E., Cooper, D. N., Sebat, J. L., Iakoucheva, L. M., Mooney, S. D., & Predrag Radivojac, A. (2017) · Bioinformatics · doi:10.1093/bioinformatics/btx272 · Cited by 90
“This resulted in 3 42¼126 PSSM features and 3 2 3 9¼162 AL2CO conservation features.”
MethodVilla, C. E., Cheroni, C., Dotter, C. P., López-Tóbon, A., Oliveira, B., Sacco, R., Yahya, A. Ç., Morandell, J., Gabriele, M., Tavakoli, M. R., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110615 · Cited by 92
Support for calcium channel gene defects in autism spectrum disorders
Lu, A. T.-H., Dai, X., Martínez-Agosto, J. A., & Cantor, R. M. (2012) · Molecular Autism · doi:10.1186/2040-2392-3-18 · Cited by 100
“Recently, exon sequencing has identified de novo mutations in two other CCGs, CACNA1D and CACNA1E, in a sample of 209 sporadic ASD families that have no previous history of ASD or its related phenotypes [20].”
BackgroundIntellectual disability is associated with increased runs of homozygosity in simplex autism
Gamsiz, E. D., Viscidi, E. W., Frederick, A. M., Nagpal, S., Sanders, S. J., Murtha, M. T., Schmidt, M., Triche, E. W., Geschwind, D. H., State, M. W., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.06.004 · Cited by 79
“Further, we investigated whether there are homozygous, rare deleterious coding variants in any of the genes within intervals in which ROH was more common in affected probands than in their control siblings (Table S4) by using available exome-sequencing data for the SSC data set.(18,19,20) Although sequence data were o…”
MethodFocal Scn1a knockdown induces cognitive impairment without seizures
Bender, A. C., Natola, H., Ndong, C., Holmes, G. L., Scott, R. C., & Lenck‐Santini, P. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.12.021 · Cited by 90
Warburg effect hypothesis in autism Spectrum disorders
Vallée, A., & Vallée, J.-N. (2018) · Molecular Brain · doi:10.1186/s13041-017-0343-6 · Cited by 92
“Several studies has shown a main role of numerous compounds of the WNT/β-catenin pathway in ASD, such as WNT1 [67], WNT2 [61], WNT3 [68], WNT7A [69], APC [70–72], β-catenin [8, 73], TCF4 [74, 75] and TCF7 [76].”
Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons
Xu, Q., Liu, Y.-Y., Wang, X., Tan, G., Li, H., Hulbert, S. W., Li, C., Hu, C.-C., Xiong, Z., Xu, X., et al. (2018) · Molecular Autism · doi:10.1186/s13229-018-0244-2 · Cited by 92
Delling, J. P., & Boeckers, T. M. (2021) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-021-09397-8 · Cited by 104
“It has been estimated that 10–20% of ASD patients are affected by rare point mutations or CNVs, most of them de novo [14, 16, 19].”
BackgroundThe genetic landscape of autism spectrum disorders
Rosti, R. Ö., Sadek, A. A., Vaux, K. K., & Gleeson, J. G. (2013) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.12278 · Cited by 95
Gui, H., Schriemer, D., Cheng, W., Chauhan, R. K., Antiñolo, G., Berrios, C., Bleda, M., Brooks, A. S., Brouwer, R. W. W., Burns, A. J., et al. (2017) · Genome biology · doi:10.1186/s13059-017-1174-6 · Cited by 94
A Pilot Proteomic Analysis of Salivary Biomarkers in Autism Spectrum Disorder
Wetie, A. G. N., Wormwood, K. L., Russell, S., Ryan, J. P., Darie, C. C., & Woods, A. G. (2015) · Autism Research · doi:10.1002/aur.1450 · Cited by 90
“Based on these studies, ASD likely has multiple causes and subtypes [O’Roak et al., 2012].”
BackgroundPuthussery, T., Venkataramani, S., Gayet‐Primo, J., Smith, R. G., & Taylor, W. R. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1249-13.2013 · Cited by 90
“, 2008), as well as autism spectrum disorders (Han et al., 2012; O’Roak et al., 2012).”
BackgroundDougherty, J. D., Maloney, S. E., Wozniak, D. F., Rieger, M. A., Sonnenblick, L. I., Coppola, G., Mahieu, N. G., Zhang, J., Cai, J., Patti, G. J., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4762-12.2013 · Cited by 88
“The paradigms of the previous era of human genetics, typified by observations of a suspicious looking variant in a few families and nothing similar in a few hundred families, are insufficient to cope with the overwhelming catalogs of variants being discovered now (Neale et al., 2012; O’Roak et al., 2012; Sanders et al…”
BackgroundHu, V. W., Sarachana, T., Sherrard, R. M., & Kocher, K. M. (2015) · Molecular Autism · doi:10.1186/2040-2392-6-7 · Cited by 93
“Because of the strong heritability of ASD based on monozygotic twin and sibling studies [2,3], there have been extensive searches for genetic mutations and variations that may cause ASD [4-13].”
BackgroundProgress in the Genetics of Polygenic Brain Disorders: Significant New Challenges for Neurobiology
McCarroll, S. A., & Hyman, S. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.046 · Cited by 90
News from the Protein Mutability Landscape
Hecht, M., Bromberg, Y., & Rost, B. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.07.028 · Cited by 88
“[6] O'RoakBJ, Vives L,GirirajanS, KarakocE, KrummN,CoeBP, et al.”
BackgroundBirtele, M., Dosso, A. D., Xu, T., Nguyen, T. N., Wilkinson, B., Hosseini, N., Nguyen, S. C., Urenda, J., Knight, G. T., Rojas, C., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01477-3 · Cited by 101
The protomap is propagated to cortical plate neurons through an Eomes -dependent intermediate map
Elsen, G. E., Hodge, R. D., Bedogni, F., Daza, R. A. M., Nelson, B. R., Shiba, N., Reiner, S. L., & Hevner, R. F. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209076110 · Cited by 87
“Recently, exonic de novo mutations of TBR1 were associated with autism and ID, suggesting TBR1 mutations contribute to the risk of these disorders (43, 44).”
BackgroundSchizophrenia genetics: emerging themes for a complex disorder
Kavanagh, D. H., Tansey, K. E., O’Donovan, M. C., & Owen, M. J. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.148 · Cited by 93
Genome-scale neurogenetics: methodology and meaning
McCarroll, S. A., Feng, G., & Hyman, S. E. (2014) · Nature Neuroscience · doi:10.1038/nn.3716 · Cited by 89
Delahaye‐Duriez, A., Srivastava, P. K., Shkura, K., Langley, S. R., Laaniste, L., Moreno‐Moral, A., Danis, B., Mazzuferi, M., Foerch, P., Gazina, E. V., et al. (2016) · Genome biology · doi:10.1186/s13059-016-1097-7 · Cited by 90
“At the level of protein-protein interactions, several studies based on whole-exome sequencing trio analysis of neurodevelopmental disease have reported that genes with de novo loss-of-function mutations code for highly interconnected protein networks for autism [63], schizophrenia [61] and EE [14].”
BackgroundMethodChromatin Remodeling Complex NuRD in Neurodevelopment and Neurodevelopmental Disorders
Hoffmann, A., & Spengler, D. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00682 · Cited by 92
Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders
Caracci, M. O., Ávila, M. E., Espinoza-Cavieres, F. A., López, H. R., Ugarte, G. D., & Ferrari, G. V. D. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.764756 · Cited by 86
Goh, G., & Choi, M. (2012) · Genomics & Informatics · doi:10.5808/gi.2012.10.4.214 · Cited by 98
“A series of studies involving autism trios and quartets recently demonstrated that rare de novo mutations were associated with the risk of autism and identified multiple de novo mutations in SCN2A, KATNAL2, and CHD8, implicating these genes in the genetic etiology underlying autism [9-11].”
BackgroundIn search of low-frequency and rare variants affecting complex traits
Panoutsopoulou, K., Tachmazidou, I., & Zeggini, E. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt376 · Cited by 90
A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders
Ngo, K. J., Rexach, J. E., Lee, H., Petty, L. E., Perlman, S., Valera, J. M., Deignan, J. L., Mao, Y., Aker, M., Posey, J. E., et al. (2019) · Human Mutation · doi:10.1002/humu.23946 · Cited by 90
Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder
Mullegama, S. V., Rosenfeld, J. A., Orellana, C., van Bon, B. W. M., Halbach, S. S., Repnikova, E. A., Brick, L., Li, C. C., Dupuis, L., Rosello, M., et al. (2013) · European Journal of Human Genetics · doi:10.1038/ejhg.2013.67 · Cited by 85
Candidate and non-candidate genes in behavior genetics
Flint, J., & Munafo, M. R. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.07.005 · Cited by 85
Guan, J., Cai, J. J., Ji, G., & Sham, P. C. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0488-4 · Cited by 86
Neggers, Y. H. (2014) · ISRN Nutrition · doi:10.1155/2014/514026 · Cited by 101
“Though ASD is considered an autoimmune disease [39, 41] it also appears to have several important diet and nutrient related risk factors.”
BackgroundChen, X. S., Reader, R. H., Hoischen, A., Veltman, J. A., Simpson, N. H., Francks, C., Newbury, D. F., & Fisher, S. E. (2017) · Scientific Reports · doi:10.1038/srep46105 · Cited by 81
Ey, E., Yang, M., Katz, A. M., Woldeyohannes, L., Silverman, J. L., Leblond, C. S., Fauré, P., Torquet, N., Sourd, A. L., Bourgeron, T., et al. (2012) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2012.00849.x · Cited by 84
A genetic model for neurodevelopmental disease
Coe, B. P., Girirajan, S., & Eichler, E. E. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.04.007 · Cited by 81
Self-citationFirst glimpses of the neurobiology of autism spectrum disorder
Sanders, S. J. (2015) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2015.10.002 · Cited by 84
Kobayashi, Y., Tohyama, J., Kato, M., Akasaka, N., Magara, S., Kawashima, H., Ohashi, T., Shiraishi, H., Nakashima, M., Saitsu, H., et al. (2016) · Brain and Development · doi:10.1016/j.braindev.2015.09.011 · Cited by 84
“Regarding our study, de novo mutations in TBL1XR1 have been found in patients with ASD [38,39], and de novo mutations in GRIN1 or SETD5 were identified in patients with nonsyndromic ID [40,41].”
BackgroundSoto, D., Olivella, M., Grau, C., Armstrong, J., Alcon, C., Gasull, X., Santos‐Gómez, A., Locubiche, S., de Salazar, M. G., García-Díaz, R., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aaw0936 · Cited by 86
“In agreement with the proposed functional impact of de novomutations of GluN2B subunit, previous studies have associated de novomutations of GRIN2B with severe phenotypic alterations (6, 14, 15, 37).”
ResultBroad domains of histone H3 lysine 4 trimethylation in transcriptional regulation and disease
Park, S., Kim, G. W., Kwon, S. H., & Lee, J. (2020) · FEBS Journal · doi:10.1111/febs.15219 · Cited by 88
Wang, C.-C., Held, R. G., & Hall, B. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083941 · Cited by 90
“Neurodevelopmental disorders such as non-syndromic forms of ID and ASD involve disruptions in excitatory synaptic function.”
BackgroundInfluentialGABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy
Yoo, Y., Jung, J., Lee, Y., Lee, Y., Cho, H., Na, E., Hong, J., Kim, E., Lee, J. S., Lee, J., et al. (2017) · Annals of Neurology · doi:10.1002/ana.25032 · Cited by 88
“70; Fisher’s exact test).(19,20,51) However, we cannot exclude the possibility that these mutations may indirectly affect the efficacy of downstream signaling cascades downstream of GABABR.”
BackgroundThe transcriptional regulatorADNPlinks the BAF (SWI/SNF) complexes with autism
Vandeweyer, G., Helsmoortel, C., Dijck, A. V., Silfhout, A. T. V., Coe, B. P., Bernier, R., Gerdts, J. A., Rooms, L., van den Ende, J., Bakshi, M., et al. (2014) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31413 · Cited by 81
Self-citationHunting human disease genes: lessons from the past, challenges for the future
Brunham, L. R., & Hayden, M. R. (2013) · Human Genetics · doi:10.1007/s00439-013-1286-3 · Cited by 84
“Four recent studies reported exome sequencing of ‘trios’ (affected child and parents) or ‘quads’ (affected child, unaffected sibling and parents) in families with autism spectrum disorder (ASD) (Neale et al. 2012; O’Roak et al. 2012; Sanders et al. 2012; Iossifov et al. 2012).”
BackgroundBrief Report: SETD2 Mutation in a Child with Autism, Intellectual Disabilities and Epilepsy
Lumish, H. S., Wynn, J., Devinsky, O., & Chung, W. K. (2015) · Journal of Autism and Developmental Disorders · doi:10.1007/s10803-015-2484-8 · Cited by 82
“Our patient is phenotypically similar to the female patient with a frameshift mutation in SETD2, both with a history of failure to thrive, non-febrile seizures, motor delays, low-normal non-verbal IQs, and macrocephaly (SFARI Base) (O’Roak et al. 2012a).”
BackgroundInfluentialSuhl, J. A., Chopra, P., Anderson, B. R., Bassell, G. J., & Warren, S. T. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu272 · Cited by 81
Chu, B. W., Kovary, K. M., Guillaume, J., Chen, L., Teruel, M. N., & Wandless, T. J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.499350 · Cited by 80
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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