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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Most proteins encoded by ASD risk genes are involved either in synaptic structure and function or chromatin modification and regulation of gene expression.
“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]
The paper describes ASD-associated mutations in genes involved in synapse formation and in a chromatin-remodeling protein network (Abstract; page not provided). But it reports that 39% of the severe or disruptive de novo mutations studied map to that network; it does not establish that most proteins encoded by ASD risk genes fall into the two categories claimed. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCNVs and SNPs have both been reported to play a major role in autism incidence.
“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 612 Simons Simplex Collection families, analysis of publicly released whole-exome sequence data showed a modest trend toward an excess of biallelic inherited rare protein-altering variants with MAF below 1% in cases (8/612) compared with control siblings (2/419) in at least one screened gene, with p=0.21 by two-tailed Fisher's exact test.
“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
A common theme for ASD mutations in general may be partial loss of gene function and/or dosage sensitivity.
“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
Collectively, these papers show that rare SNVs play a significant role in ASD genetic liability.
“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]
Exome and whole-genome sequencing studies estimate at least another ∼6% contribution to ASD risk.
“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]
The SON-exomes list comprises 65 genes disrupted by de novo nonsense, frameshift or splice-site point mutations in autism probands from three other studies (Sanders et al., O'Roak et al., Neale et al.).
“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]
Genetic approaches have identified causes for more than 1,000 Mendelian and fewer non-Mendelian forms of neurodevelopmental disorders, including intellectual disability, ASD, epilepsy, and schizophrenia.
“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]
Literature-curated PPI seed-based networks have identified convergence of ASD risk genes.
“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]
A highly interconnected PPI subnetwork exists among rare de novo variants in ASD.
“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]
Many strong neurobiological candidates have emerged from genes disrupted by de novo mutations, including previously identified ASD/ID genes.
“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]
The strongest effects are observed for de novo loss-of-function or truncating mutations.
“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]
Exome sequencing of ASD/ID families has revealed a significant excess of de novo mutations in probands compared with unaffected siblings and has identified novel candidate genes.
“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]
Sporadic cases of autism spectrum disorder and intellectual disability are enriched for disruptive de novo mutations.
“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]
DYRK1A has three truncating mutations in autism probands and de novo structural variants in ID probands.
“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]
Only three genes, CHD8, SCN2A, and SYNGAP1, had two independent truncating de novo mutations in any single study, and no gene had more than three mutations.
“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]
One de novo frameshift of ARID1B was found in a sporadic ASD case.
“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]
One mechanism mediating the paternal age effect on ASD risk is the higher rate of de novo single-nucleotide variants and copy number variants with advancing paternal age.
“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]
TBR1 has been implicated in ASD and intellectual disability.
“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]
Recent studies of rare variants find it challenging to distinguish risk variation from the background stochastic noise.
“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]
De novo loss-of-function mutations in ADNP had previously been reported in two autism spectrum disorder patients by whole-exome sequencing and targeted resequencing, but those studies did not establish locus-specific significance for causality.
“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]
De novo mutations have emerged as substantial contributors to ASD risk.
“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]
CHD8 is one of the high-penetrance ASD risk genes recently identified by sequencing studies.
“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]
Recent exome sequencing studies reported no truncating coding-sequence variation within SHANK1 and SHANK3.
“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]
Recent exome sequencing studies reported only one de novo SHANK2 mutation out of 965 patients.
“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]
ASD is highly polygenic, with estimates from de novo exonic mutations ranging from 400-1000 genes.
“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]
De novo exonic mutations in SCN2A, KATNAL2, and CHD8 play roles in the pathogenesis of ASD.
“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]
All three studies noted an increased rate of de novo exonic mutations in older parents, with the mutations generally being of paternal origin.
“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]
Only a minority of ASD cases had a de novo putatively functional variant.
“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]
Simplex and multiplex ASD pedigrees show relatively similar de novo mutation rates for SV and exonic variation.
“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]
Projections for ASD and SCZ suggest that variation at hundreds of different genes will ultimately be shown to be involved.
“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]
The published results for ASD 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.
“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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Moldin, S. O. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.4.621 · Cited by 27 · see citing works
Talati, A., Fyer, A. J., & Weissman, M. M. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4002114 · Cited by 21 · see citing works
Disease Gene Prioritization Based on Topological Similarity in Protein-Protein Interaction Networks
Erten, S., Bebek, G., & Koyutürk, M. (2011) · Lecture notes in computer science · doi:10.1007/978-3-642-20036-6_7 · Cited by 13 · see citing works
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A general framework for estimating the relative pathogenicity of human genetic variants
Kircher, M., Witten, D. M., Jain, P., O'Roak, B. J., Cooper, G. M., & Shendure, J. (2014) · Nature Genetics · doi:10.1038/ng.2892 · Cited by 6,183 · see citing works
Self-citationComing of age: ten years of next-generation sequencing technologies
Goodwin, S., McPherson, J. D., & McCombie, W. R. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.49 · Cited by 4,352 · see citing works
The contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., et al. (2014) · Nature · doi:10.1038/nature13908 · Cited by 2,585 · see citing works
Self-citationSynaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · see citing works
Lai, M.-C., Lombardo, M. V., & Baron-Cohen, S. (2014) · The Lancet · doi:10.1016/s0140-6736(13)61539-1 · Cited by 2,371 · see citing works
Rate of de novo mutations and the importance of father’s age to disease risk
Kong, A., Frigge, M. L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S. A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., et al. (2012) · Nature · doi:10.1038/nature11396 · Cited by 2,134 · see citing works
“Applying (5) eliminated 1,285 candidate mutations (Supplementary Information).”
InfluentialDe novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084 · see citing works
Lord, C., Brugha, T. S., Charman, T., Cusack, J., Dumas, G., Frazier, T., Jones, E. J. H., Jones, R. M., Pickles, A., State, M. W., et al. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0138-4 · Cited by 1,859 · see citing works
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734 · see citing works
De novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · see citing works
Prevalence and architecture of de novo mutations in developmental disorders
Study, D. D. D. (2017) · Nature · doi:10.1038/nature21062 · Cited by 1,480 · see citing works
Diagnostic exome sequencing in persons with severe intellectual disability
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206524 · Cited by 1,546 · see citing works
Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci
Sanders, S. J., He, X., Willsey, A. J., Ercan-Sencicek, A. G., Samocha, K. E., Cicek, A. E., Murtha, M. T., Bal, V. H., Bishop, S. L., Dong, S., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.016 · Cited by 1,430 · see citing works
“…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).”
BackgroundInfluentialDe novo mutations in epileptic encephalopathies
Epi4K Consortium, & Epilepsy Phenome/Genome Project (2013) · Nature · doi:10.1038/nature12439 · Cited by 1,514 · see citing works
De Novo Gene Disruptions in Children on the Autistic Spectrum
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y.-H., Narzisi, G., Leotta, A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.04.009 · Cited by 1,446 · see citing works
A polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385 · see citing works
Most genetic risk for autism resides with common variation
Gaugler, T., Klei, L., Sanders, S. J., Bodea, C. A., Goldberg, A. P., Lee, A. B., Mahajan, M., Manaa, D., Pawitan, Y., Reichert, J., et al. (2014) · Nature Genetics · doi:10.1038/ng.3039 · Cited by 1,239 · see citing works
“and (3) Swedish twins of 9–12 years of age”
BackgroundMultiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders
O’Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., Carvill, G., Kumar, A., Lee, C., Ankenman, K., et al. (2012) · Science · doi:10.1126/science.1227764 · Cited by 1,240 · see citing works
Self-citationGuidelines for investigating causality of sequence variants in human disease
MacArthur, D. G., Manolio, T. A., Dimmock, D. P., Rehm, H. L., Shendure, J., Abecasis, G. R., Adams, D. R., Altman, R. B., Antonarakis, S. E., Ashley, E. A., et al. (2014) · Nature · doi:10.1038/nature13127 · Cited by 1,224 · see citing works
Self-citationSex differences in autism spectrum disorders
Werling, D. M., & Geschwind, D. H. (2013) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32835ee548 · Cited by 1,245 · see citing works
Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery
Lin, S., Staahl, B. T., Alla, R. K., & Doudna, J. A. (2014) · eLife · doi:10.7554/elife.04766 · Cited by 1,189 · see citing works
“To test these effects at other genomic loci, we programmed Cas9 RNPs to target the DYRK1 gene, which is important for brain development, autism and Downs Syndrome (Arron et al., 2006; Fotaki et al., 2002; O'Roak et al., 2012).”
MethodLarge-scale discovery of novel genetic causes of developmental disorders
Study, T. D. D. D. (2015) · Nature · doi:10.1038/nature14135 · Cited by 1,124 · see citing works
Genetic architectures of psychiatric disorders: the emerging picture and its implications
Sullivan, P. F., Daly, M. J., & O'Donovan, M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3240 · Cited by 1,177 · see citing works
Genome sequencing identifies major causes of severe intellectual disability
Gilissen, C., Hehir-Kwa, J. Y., Thung, D. T., van de Vorst, M., van Bon, B. W. M., Willemsen, M. H., Kwint, M., Janssen, I. M., Hoischen, A., Schenck, A., et al. (2014) · Nature · doi:10.1038/nature13394 · Cited by 1,125 · see citing works
Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism
Parikshak, N. N., Luo, R., Zhang, A., Won, H., Lowe, J. K., Chandran, V., Horvath, S., & Geschwind, D. H. (2013) · Cell · doi:10.1016/j.cell.2013.10.031 · Cited by 1,039 · see citing works
Zamponi, G., Striessnig, J., Koschak, A., & Dolphin, A. (2015) · Pharmacological Reviews · doi:10.1124/pr.114.009654 · Cited by 1,004 · see citing works
“In addition, de novo CACNA1D mutations have also been reported as high-riskmutations in two patients with sporadic autism and intellectual disability (Iossifov et al., 2012; O’Roak et al., 2012).”
BackgroundShared molecular neuropathology across major psychiatric disorders parallels polygenic overlap
Gandal, M. J., Haney, J. R., Parikshak, N. N., Leppa, V., Ramaswami, G., Hartl, C., Schork, A. J., Appadurai, V., Buil, A., Werge, T. M., et al. (2018) · Science · doi:10.1126/science.aad6469 · Cited by 1,095 · see citing works
Rauch, A., Wieczorek, D., Graf, E., Wieland, T., Endele, S., Schwarzmayr, T., Albrecht, B., Bartholdi, D., Beygo, J., Di Donato, N., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61480-9 · Cited by 1,041 · see citing works
From the genetic architecture to synaptic plasticity in autism spectrum disorder
Bourgeron, T. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3992 · Cited by 975 · see citing works
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.03.018 · Cited by 969 · see citing works
Self-citationThe Next-Generation Sequencing Revolution and Its Impact on Genomics
Koboldt, D. C., Steinberg, K. M., Larson, D. E., Wilson, R. K., & Mardis, E. R. (2013) · Cell · doi:10.1016/j.cell.2013.09.006 · Cited by 1,039 · see citing works
“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).”
Willsey, A. J., Sanders, S. J., Li, M., Dong, S., Tebbenkamp, A. T., Muhle, R. A., Reilly, S. K., Lin, L., Fertuzinhos, S., Miller, J. A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.020 · Cited by 934 · see citing works
“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 Gockley,1 Abha R. Gup…”
InfluentialGenic Intolerance to Functional Variation and the Interpretation of Personal Genomes
Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S., & Goldstein, D. B. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003709 · Cited by 901 · see citing works
“We further evaluate how well this approach prioritizes candidate de novo mutations identified in patient genomes [9–15].”
An Overview of Autism Spectrum Disorder, Heterogeneity and Treatment Options
Masi, A., DeMayo, M. M., Glozier, N., & Guastella, A. J. (2017) · Neuroscience Bulletin · doi:10.1007/s12264-017-0100-y · Cited by 987 · see citing works
“Large numbers of genes implicated in ASD are thought to converge on common pathways affecting neuronal and synaptic homeostasis [61], and play critical roles in fundamental developmental pathways [39, 59].”
BackgroundA framework for the interpretation of de novo mutation in human disease
Samocha, K. E., Robinson, E. B., Sanders, S. J., Stevens, C., Sabo, A., McGrath, L. M., Kosmicki, J. A., Rehnström, K., Mallick, S., Kirby, A., et al. (2014) · Nature Genetics · doi:10.1038/ng.3050 · Cited by 979 · see citing works
Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders
Lee, H., Deignan, J. L., Dorrani, N., Strom, S. P., Kantarci, S., Quintero‐Rivera, F., Das, K., Toy, T. L., Harry, B., Yourshaw, M., et al. (2014) · JAMA · doi:10.1001/jama.2014.14604 · Cited by 973 · see citing works
“DD + hypotonia 28/111 25 (18-34) 2/27 7 (1-24) 26/80 33 (23-43) 0/4 0 (0-55)”
InfluentialDe novo mutations in histone-modifying genes in congenital heart disease
Zaidi, S., Choi, M., Wakimoto, H., Ma, L., Jiang, J., Overton, J. D., Romano-Adesman, A., Bjornson, R. D., Breitbart, R. E., Brown, K. K., et al. (2013) · Nature · doi:10.1038/nature12141 · Cited by 934 · see citing works
Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
Pejaver, V., Urresti, J., Lugo-Martinez, J., Pagel, K. A., Lin, G. N., Nam, H.-J., Mort, M., Cooper, D. N., Sebat, J., Iakoucheva, L. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19669-x · Cited by 923 · see citing works
Advancing the understanding of autism disease mechanisms through genetics
de la Torre-Ubieta, L., Won, H., Stein, J. L., & Geschwind, D. H. (2016) · Nature Medicine · doi:10.1038/nm.4071 · Cited by 827 · see citing works
Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development
Bernier, R., Golzio, C., Xiong, B., Stessman, H. A., Coe, B. P., Penn, O., Witherspoon, K., Gerdts, J., Baker, C., Vulto-van Silfhout, A. T., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.017 · Cited by 798 · see citing works
Self-citationDe novo mutations in human genetic disease
Veltman, J. A., & Brunner, H. G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3241 · Cited by 845 · see citing works
“Patients with an ASD, O’Roak et al.(15) 189 225 1.”
BackgroundCoe, B. P., Witherspoon, K., Rosenfeld, J. A., van Bon, B. W. M., Vulto-van Silfhout, A. T., Bosco, P., Friend, K. L., Baker, C., Buono, S., Vissers, L. E. L. M., et al. (2014) · Nature Genetics · doi:10.1038/ng.3092 · Cited by 720 · see citing works
Self-citationGenetic studies in intellectual disability and related disorders
Vissers, L. E. L. M., Gilissen, C., & Veltman, J. A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg3999 · Cited by 761 · see citing works
Rare-disease genetics in the era of next-generation sequencing: discovery to translation
Boycott, K. M., Vanstone, M. R., Bulman, D. E., & MacKenzie, A. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3555 · Cited by 760 · see citing works
Genetics of autism spectrum disorders
Geschwind, D. H. (2011) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2011.07.003 · Cited by 696 · see citing works
Leblond, C. S., Nava, C., Polge, A., Gauthier, J., Huguet, G., Lumbroso, S., Giuliano, F., Stordeur, C., Depienne, C., Mouzat, K., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004580 · Cited by 630 · see citing works
“[32,36,37] and no truncating coding-sequence variation within SHANK1 and SHANK3.”
BackgroundDisentangling the heterogeneity of autism spectrum disorder through genetic findings
Jeste, S. S., & Geschwind, D. H. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.278 · Cited by 644 · see citing works
“8,9,13 Exome or genome sequencing moves genetic analysis of patients to the level of the single base pair, expanding testing beyond individual or small groups of related genes, such as those usually detected by CMA.”
Excess of rare, inherited truncating mutations in autism
Krumm, N., Turner, T. N., Baker, C., Vives, L., Mohajeri, K., Witherspoon, K., Raja, A., Coe, B. P., Stessman, H. A., He, Z.-X., et al. (2015) · Nature Genetics · doi:10.1038/ng.3303 · Cited by 587 · see citing works
Self-citationPhenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants
Girirajan, S., Rosenfeld, J. A., Coe, B. P., Parikh, S., Friedman, N., Goldstein, A., Filipink, R. A., McConnell, J. S., Angle, B., Meschino, W. S., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200395 · Cited by 621 · see citing works
Self-citationJacquemont, S., Coe, B. P., Hersch, M., Duyzend, M. H., Krumm, N., Bergmann, S., Beckmann, J. S., Rosenfeld, J. A., & Eichler, E. E. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.02.001 · Cited by 605 · see citing works
“The second consisted of 31 autism quads and 168 trios.(17) Probands and siblings with fewer than 20 million reads and parents with fewer”
BackgroundSelf-citationCopy number variation detection and genotyping from exome sequence dataPreprint
Krumm, N., Sudmant, P. H., Ko, A., O’Roak, B. J., Malig, M., Coe, B. P., NHLBI Exome Sequencing Project, Quinlan, A. R., Nickerson, D. A., & Eichler, E. E. (2012) · Genome Research · doi:10.1101/gr.138115.112 · Cited by 639 · see citing works
Self-citationAutistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission
Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., Rubenstein, J. L., Scheuer, T., de la Iglesia, H. O., & Catterall, W. A. (2012) · Nature · doi:10.1038/nature11356 · Cited by 643 · see citing works
Searching for missing heritability: Designing rare variant association studies
Zuk, O., Schaffner, S. F., Samocha, K., Do, R., Hechter, E., Kathiresan, S., Daly, M. J., Neale, B. M., Sunyaev, S. R., & Lander, E. S. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322563111 · Cited by 635 · see citing works
“For example, CHD8 was associated with autism with mental retardation (prevalence < 1/300) (52) based on the observation of de novo disruptive mutations in 3 of 1,078 cases (53, 54).”
BackgroundFu, J. M., Satterstrom, F. K., Peng, M., Brand, H., Collins, R. L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S. P., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01104-0 · Cited by 640 · see citing works
The bowel and beyond: The enteric nervous system in neurological disorders
Rao, M., & Gershon, M. D. (2016) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.107 · Cited by 629 · see citing works
A scored human protein–protein interaction network to catalyze genomic interpretation
Li, T., Wernersson, R., Hansen, R. B., Horn, H., Mercer, J., Slodkowicz, G., Workman, C. T., Rigina, O., Rapacki, K., Stærfeldt, H., et al. (2016) · Nature Methods · doi:10.1038/nmeth.4083 · Cited by 630 · see citing works
Ubiquitylation at the crossroads of development and disease
Rapé, M. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.83 · Cited by 608 · see citing works
Revising the human mutation rate: implications for understanding human evolution
Scally, A., & Durbin, R. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3295 · Cited by 610 · see citing works
A spectral approach integrating functional genomic annotations for coding and noncoding variants
Ionita‐Laza, I., McCallum, K., Xu, B., & Buxbaum, J. D. (2016) · Nature Genetics · doi:10.1038/ng.3477 · Cited by 588 · see citing works
“In total for ASD, we have n = 2,027 such mutations among which 1, 753 are missense [22, 23, 24, 25, 26].”
BackgroundThe valproic acid-induced rodent model of autism
Nicolini, C., & Fahnestock, M. L. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.04.017 · Cited by 594 · see citing works
Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation
Michaelson, J. J., Shi, Y., Gujral, M., Zheng, H., Malhotra, D., Jin, X., Jian, M., Liu, G., Greer, D., Bhandari, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.11.019 · Cited by 544 · see citing works
“…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).”
InfluentialSomatic mutation, genomic variation, and neurological disease
Poduri, A., Evrony, G. D., Cai, X., & Walsh, C. A. (2013) · Science · doi:10.1126/science.1237758 · Cited by 584 · see citing works
Autism spectrum disorder: neuropathology and animal models
Varghese, M., Keshav, N., Jacot-Descombes, S., Warda, T., Wicinski, B., Dickstein, D. L., Harony-Nicolas, H., De Rubeis, S., Drapeau, E., Buxbaum, J. D., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1736-4 · Cited by 536 · see citing works
Revisiting an Old Riddle: What Determines Genetic Diversity Levels within Species?
Leffler, E. M., Bullaughey, K., Matute, D. R., Meyer, W. K., Ségurel, L., Venkat, A., Andolfatto, P., & Przeworski, M. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001388 · Cited by 577 · see citing works
“, in humans [79,80]).”
Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., Rippey, C., Shahin, H., Braff, D., Cadenhead, K. S., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.049 · Cited by 536 · see citing works
Genetic Causes and Modifiers of Autism Spectrum Disorder
Rylaarsdam, L. E., & Guemez‐Gamboa, A. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00385 · Cited by 575 · see citing works
Genetic architecture in autism spectrum disorder
Devlin, B., & Scherer, S. W. (2012) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2012.03.002 · Cited by 545 · see citing works
From neural development to cognition: unexpected roles for chromatin
Ronan, J. L., Wu, W., & Crabtree, G. R. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3413 · Cited by 544 · see citing works
Whole-genome sequencing of quartet families with autism spectrum disorder
Yuen, R. K. C., Thiruvahindrapuram, B., Merico, D., Walker, S., Tammimies, K., Hoang, N., Chrysler, C., Nalpathamkalam, T., Pellecchia, G., Liu, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3792 · Cited by 514 · see citing works
Gupta, S., Ellis, S. E., Ashar, F. N., Moes, A., Bader, J. S., Zhan, J., West, A. B., & Arking, D. E. (2014) · Nature Communications · doi:10.1038/ncomms6748 · Cited by 504 · see citing works
“In addition to the SFARI list of genes, we also integrated genes associated with rare de novo variation (RDNV) and genes involved in intellectual disability (ID) compiled from four published whole-exome sequencing studies 5,7,8,23 and review articles 24 (Supplementary Data 7).”
InfluentialAutism-related deficits via dysregulated eIF4E-dependent translational control
Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., et al. (2013) · Nature · doi:10.1038/nature11628 · Cited by 522 · see citing works
Neurodevelopmental disorders—the history and future of a diagnosticconcept
Morris-Rosendahl, D. J., & Crocq, M. (2020) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2020.22.1/macrocq · Cited by 525 · see citing works
Modeling Autism by SHANK Gene Mutations in Mice
Jiang, Y.-H., & Ehlers, M. D. (2013) · Neuron · doi:10.1016/j.neuron.2013.03.016 · Cited by 488 · see citing works
Inherited and de novo genetic risk for autism impacts shared networks
Ruzzo, E. K., Pérez-Cano, L., Jung, J.-Y., Wang, L.-K., Kashef-Haghighi, D., Hartl, C., Singh, C., Xu, J., Hoekstra, J. N., Leventhal, O., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.015 · Cited by 457 · see citing works
“, 2007), and de novo frameshift, splice acceptor, splice donor, or nonsense variants (collectively referred to as protein-truncating variants [PTVs]) (De Rubeis et al., 2014; Iossifov et al., 2012, 2014; O’Roak et al., 2012; Sanders et al., 2012) that increase ASD risk and account for an estimated 3%–5% of ASD cases (…”
BackgroundJiang, Y.-H., Yuen, R. K. C., Jin, X., Wang, M., Chen, N., Wu, X., Ju, J., Mei, J., Shi, Y., He, M., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.06.012 · Cited by 474 · see citing works
“We evaluated the approach by using the validation results of (1) all genomic de novo SNVs in one family (2-1266) and (2) Sanger”
MethodDeficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects
Kim, H.-J., Cho, M.-H., Shim, W. H., Kim, J. K., Jeon, E.-Y., Kim, D.-H., & Yoon, S.-Y. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.103 · Cited by 475 · see citing works
Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders
Sullivan, P. F., & Geschwind, D. H. (2019) · Cell · doi:10.1016/j.cell.2019.01.015 · Cited by 452 · see citing works
“Despite these limitations, several studies in ASD and SCZ highlight the power of using transcriptional networks based on normal human brain tissue across development or brain regions ormore generalized PPIs (Hormozdiari et al., 2015; Li et al., 2014; Lin et al., 2015) to identify molecular pathways, developmental epoc…”
BackgroundPredicting the clinical impact of human mutation with deep neural networks
Sundaram, L., Gao, H., Padigepati, S. R., McRae, J. F., Li, Y., Kosmicki, J. A., Fritzilas, N., Hakenberg, J., Dutta, A., Shon, J. C., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0167-z · Cited by 482 · see citing works
Gene hunting in autism spectrum disorder: on the path to precision medicine
Geschwind, D. H., & State, M. W. (2015) · The Lancet Neurology · doi:10.1016/s1474-4422(15)00044-7 · Cited by 481 · see citing works
Sequence Kernel Association Tests for the Combined Effect of Rare and Common Variants
Ionita-Laza, I., Lee, S., Makarov, V., Buxbaum, J. D., & Lin, X. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.04.015 · Cited by 433 · see citing works
Using Whole-Exome Sequencing to Identify Inherited Causes of Autism
Yu, T. W., Chahrour, M. H., Coulter, M. E., Jiralerspong, S., Okamura-Ikeda, K., Ataman, B., Schmitz-Abe, K., Harmin, D. A., Adli, M., Malik, A. N., et al. (2013) · Neuron · doi:10.1016/j.neuron.2012.11.002 · Cited by 442 · see citing works
“An analysis of publicly released whole-exome sequence data (Iossifov et al., 2012;O’Roak et al., 2012; Sanders et al., 2012) showed amodest trend toward an excess of biallelic, inherited, rare (MAF < 1%), protein-altering variants in cases (8/612) compared to control siblings (2/419) (p = 0.”
BackgroundInfluentialDe novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia
Xu, B., Ionita-Laza, I., Roos, J. L., Boone, B., Woodrick, S., Sun, Y., Levy, S., Gogos, J. A., & Karayiorgou, M. (2012) · Nature Genetics · doi:10.1038/ng.2446 · Cited by 442 · see citing works
De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies
Appenzeller, S., Balling, R., Barisic, N., Baulac, S., Caglayan, H., Craiu, D., De Jonghe, P., Depienne, C., Dimova, P., Djémié, T., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.08.013 · Cited by 439 · see citing works
New insights into the generation and role of de novo mutations in health and disease
Acuña‐Hidalgo, R., Veltman, J. A., & Hoischen, A. (2016) · Genome biology · doi:10.1186/s13059-016-1110-1 · Cited by 451 · see citing works
“An enrichment for damaging de novo mutations has also been observed in individuals with milder phenotypes such as autism spectrum disorder without cognitive deficits [16, 18, 29, 30, 119].”
Sharma, R. K., Agarwal, A. K., Rohra, V. K., Assidi, M., Abu-Elmagd, M. M., & Turki, R. F. (2015) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-015-0028-x · Cited by 469 · see citing works
“also proposed that age-related de-novo mutations in male germ contribute to increased risk of neurodevelopmental disorders like autism [232,233].”
BackgroundThe Genetic Landscapes of Autism Spectrum Disorders
Huguet, G., Ey, E., & Bourgeron, T. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153431 · Cited by 447 · see citing works
Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders
Parikshak, N. N., Gandal, M. J., & Geschwind, D. H. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3934 · Cited by 430 · see citing works
“Genetic investigations in ASD have constructed seed-based networks with literature-curated PPIs to identify the convergence of ASD risk genes 71,73 .”
BackgroundMethodGABA system dysfunction in autism and related disorders: From synapse to symptoms
Coghlan, S., Horder, J., Inkster, B., Méndez, M. A., Murphy, D., & Nutt, D. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.07.005 · Cited by 437 · see citing works
A de novo convergence of autism genetics and molecular neuroscience
Krumm, N., O’Roak, B. J., Shendure, J., & Eichler, E. E. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.11.005 · Cited by 423 · see citing works
Self-citationO'Rawe, J., Jiang, T., Sun, G., Wu, Y., Wang, W., Hu, J., Bodily, P., Tian, L., Hakonarson, H. H., Johnson, W. E., et al. (2013) · Genome Medicine · doi:10.1186/gm432 · Cited by 443 · see citing works
“Although most studies utilizing NGS data to date have focused on ‘quads’ or ‘trios’ [47-51], studying large and/or consanguineous families can maximize the utility of filtering strategies and statistical approaches for identifying disease-contributory variants in genetic disease [52].”
BackgroundKrishnan, A., Zhang, R., Yao, V., Theesfeld, C. L., Wong, A. K., Tadych, A., Volfovsky, N., Packer, A. I., Lash, A., & Troyanskaya, O. G. (2016) · Nature Neuroscience · doi:10.1038/nn.4353 · Cited by 427 · see citing works
“These pathways and sets include CHD8 targets, chromatin remodeling genes, FMRP targets, MAPK pathway genes, post-synaptic density genes, TOP1 targets and Wnt– β -catenin pathway genes.”
BackgroundInfluentialTopoisomerases facilitate transcription of long genes linked to autism
King, I. F. G., Yandava, C., Mabb, A. M., Hsiao, J. S., Huang, H., Pearson, B. L., Calabrese, J. M., Starmer, J., Parker, J. S., Magnuson, T., et al. (2013) · Nature · doi:10.1038/nature12504 · Cited by 430 · see citing works
Common genetic variants, acting additively, are a major source of risk for autism
Klei, L., Sanders, S. J., Murtha, M. T., Hus, V., Lowe, J. K., Willsey, A. J., Moreno-De-Luca, D., Yu, T. W., Fombonne, E., Geschwind, D., et al. (2012) · Molecular Autism · doi:10.1186/2040-2392-3-9 · Cited by 418 · see citing works
“Twin designs also fail to capture other features, such as maternal effects [49] and de novo mutations, which are an important component of ASD genetic architecture [4-11].”
InfluentialDe Novo Mutations in Moderate or Severe Intellectual Disability
Hamdan, F. F., Srour, M., Capo-Chichi, J.-M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., Diallo, O., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004772 · Cited by 419 · see citing works
“DNMs in TBR1 have been found in patients with ID and the variable presence of ASD or growth retardation [8,9,21,29,30].”
BackgroundLesch, K.-P., & Waider, J. (2012) · Neuron · doi:10.1016/j.neuron.2012.09.013 · Cited by 435 · see citing works
Regional missense constraint improves variant deleteriousness prediction
Samocha, K. E., Kosmicki, J. A., Karczewski, K. J., O’Donnell-Luria, A. H., Pierce-Hoffman, E., MacArthur, D. G., Neale, B. M., & Daly, M. J. (2017) · doi:10.1101/148353 · Cited by 351 · see citing works
Large-scale genomics unveils the genetic architecture of psychiatric disorders
Gratten, J., Wray, N. R., Keller, M. C., & Visscher, P. M. (2014) · Nature Neuroscience · doi:10.1038/nn.3708 · Cited by 363 · see citing works
The role of de novo mutations in the genetics of autism spectrum disorders
Ronemus, M., Iossifov, I., Levy, D., & Wigler, M. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3585 · Cited by 390 · see citing works
MMP ‐9 in translation: from molecule to brain physiology, pathology, and therapy
Vafadari, B., Salamian, A., & Kaczmarek, L. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13415 · Cited by 381 · see citing works
A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP
Helsmoortel, C., Vulto-van Silfhout, A. T., Coe, B. P., Vandeweyer, G., Rooms, L., van den Ende, J., Schuurs-Hoeijmakers, J. H. M., Marcelis, C. L., Willemsen, M. H., Vissers, L. E. L. M., et al. (2014) · Nature Genetics · doi:10.1038/ng.2899 · Cited by 354 · see citing works
“Variants were filtered by VariantDB (see URLs, manuscript in preparation) to exclude variants with (1) low quality, using thresholds based on correlation between NGS data and SNP-chip genotyping; (2) intronic or intergenic location, except splice sites; and (3) inheritance from the parents.”
MethodSelf-citation
- 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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