De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Open accessAbstract
Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.
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TADA requires a mutational model that accounts for gene size and sequence composition to obtain an expectation for mutations per gene given sample size.
“TADA requires a mutational model (Sanders et al., 2012; Neale et al., 2012; Samocha et al., 2014) which accounts for gene size and sequence composition to obtain an expectation for mutations per gene, given sample size.”
From Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism (2020) · cites this paper as Sanders et al., 2012
CNVs 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 [40]
Genetic studies of de novo variants have consistently supported a female protective effect against ASD.
“The possibility of a “female protective effect” (FPE) against ASD has been described extensively and has received consistent support from the results of genetic studies of de novo variants.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [5]
Many types of ASD-associated de novo variants are observed more frequently in female cases.
“Many types of ASD-associated de novo variants are observed more frequently in female cases.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [5]
Previously described differences in rare variant burden, along with preliminary evidence from studies of SNP heritability, already violate the assumption of equivalent genetic architecture between male ASD and female ASD.
“The previously described differences in rare variant burden, along with preliminary evidence from studies of SNP heritability, already violate that assumption.5, 6, 7, 8,15”
From The female protective effect against autism spectrum disorder (2022) · cites this paper as [5]
The mutation rate per gene can be estimated from its exonic length and nucleotide content and treated as known.
“For each gene, the mutation rate per gene () can be estimated from its exonic length and nucleotide content [1] and hence this quantity can be treated as known.”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [1]
The power for detecting a gene increases monotonically with increasing sample size and depends strongly on the gene's mutation rate.
“As demonstrated previously [1], the power for detecting a gene increases monotonically with increasing sample size and it depends strongly on the gene's mutation rate (Figure 1A).”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [1]
The error of mutation rate estimation is likely small.
“Although the error of mutation rate estimation is likely small [1]”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [1]
The excess of small p-values is very similar to the excess number of genes with single-hit de novo loss-of-function events in ASD subjects compared to unaffected siblings.
“There is an intriguing coincidence in the excess of small p-values - namely that it is very similar to the excess number of genes with single-hit de novo LoF events in ASD subjects compared to their unaffected siblings [1].”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [1]
The estimates of the number of ASD risk genes and average relative risk are similar to published results using somewhat different methods.
“These estimates are similar to published results using somewhat different methods [1], [2].”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [1]
Trio-based whole-exome sequencing analyses have linked many de novo loss-of-function variants to risk of neurodevelopmental conditions, including autism spectrum disorder and neurodevelopmental delay.
“analysis of trio-based whole-exome sequencing (WES) has implicated a large number of de novo loss-of-function variants contributing to risk of neurodevelopmental pathologies, including autism spectrum disorders and neurodevelopmental delay (ASD/ND) (4, 5).”
From In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes (2020) · cites this paper as [5]
ASD genetic heterogeneity is striking.
“but these studies also demonstrate striking genetic heterogeneity3-5.”
From Altered proliferation and networks in neural cells derived from idiopathic autistic individuals (2017) · cites this paper as [5]
Heritable and de novo genetic variation plays a significant role in ASD.
“Mounting evidence proposes that heritable and de novo genetic variation plays a significant role”
From Altered proliferation and networks in neural cells derived from idiopathic autistic individuals (2017) · cites this paper as [5]
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 Sanders et al., 2012
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 Sanders et al., 2012
ASD is often caused by newly arising CNVs or rare germline mutations, particularly in sperm of older fathers.
“ASD is often due to newly arising gene copy number variants (CNVs) — such as a deletion or duplication of a region of a chromosome — or a rare mutation that arises in the germ cell, particularly in sperm of older fathers5–10.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [7]
Exome sequencing of parent-offspring trios has identified de novo exonic mutations in SCN2A, KATNAL2, CHD8, FOXP1, NTNG1, GRIN2B, and LAMC3, extending the number of genes for which mutation may contribute to ASD.
“In addition, very recent exome sequencing of parent-offspring trios has identified de novo exonic mutations in SCN2A, KATNAL2, CHD8, FOXP1, NTNG1, GRIN2B, LAMC3(refs 7–9), extending further the number of genes for which mutation may contribute to ASD.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [7]
Those studies show that new sequencing technologies can greatly advance knowledge of the genetic basis of ASD.
“These studies demonstrate the ability of new sequencing technologies to significantly advance our understanding of the genetic basis of ASD.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [7]
References 7-10 used exome and whole-genome sequencing to show the importance of rare mutations in ASD and to identify new genetic mutations linked to ASD.
“References 7– 10 use exome and entire genome sequencing to demonstrate the importance of rare mutations in ASD and identify new genetic mutations associated with ASD.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [7]
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 [50]
Synonymous SNPs can affect protein folding and messenger RNA splicing, stability and structure.
“synonymous SNPs can affect protein folding and messenger RNA splicing, stability and structure57,58.”
From Immune mediators in the brain and peripheral tissues in autism spectrum disorder (2015) · cites this paper as [57]
A large-effect genetic variant is present in about 15% of ASD cases, with smaller proportions in TS, ADHD, and SCZ.
“This is particularly salient for ASD where a large effect variant is present in ~15% of cases along with smaller proportions of individuals with TS, ADHD, and SCZ (Iossifov et al., 2012; Sanders et al., 2012; Satterstrom et al., 2018c; Singh et al., 2016; Willsey et al., 2017).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Sanders et al., 2012
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 [9]
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 [8]
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 [70]
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 [27]
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 [27]
Protein-truncating de novo SNVs contribute to ASD risk for about 10-15% of probands.
“Overall, these studies suggest that protein-truncating de novo SNVs contribute to the risk of ASD for about 10–15% of probands [26,27]”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [27]
Probands have two- to threefold more disruptive de novo mutations than their siblings or a random mutation model.
“probands had two- to threefold more disruptive de novo mutations in comparison to their siblings, or to a random model of mutation [26,27].”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [27]
A small subset of de novo mutations, about 4% in unaffected individuals and about 9% in affected individuals, are disruptive.
“Moreover, a small subset of the de novo mutations (~4% for unaffected and ~9% of affected [26,27]) are disruptive”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [27]
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 [27]
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 [27]
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 [27]
Simulations based on the observed number of recurrently disrupted genes estimate that there are about 600 to 1200 ASD risk genes.
“Simulations based on the observed number of recurrently disrupted genes have estimated that there are some 600-1200 ASD risk genes (21,24,26,51).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · 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 [24]
Autosomal de novo loss-of-function single-nucleotide variants act dominantly and carry a large individual risk, with odds ratios of 20 or more for genes identified so far.
“Autosomal de novo loss-of-function SNV has been identified that acts in a dominant manner and carries a large burden for individual risk, with odds ratios of 20 or above for genes identified to date (24,26).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [24]
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 [12]
Many of the genes associated with ASD are also linked with elemental homeostasis, and genes implicated in ASD converge to specific neuronal co-expression networks especially during the same critical early developmental periods observed in this study.
“Notably, many of the genes associated with ASD are also linked with elemental homeostasis930, and it is intriguing that genes implicated in ASD converge to specific neuronal co-expression networks especially during the same critical early developmental periods we have observed in this study313233.”
From Fetal and postnatal metal dysregulation in autism (2017) · cites this paper as [30]
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 [309]
The prevalence of truncating SHANK2 coding-sequence variants in ASD is similar to that reported in four large-scale exome studies (1/965, 0.10%).
“This prevalence is similar to the one reported in the four large-scale studies in ASD using exome sequencing [32] (de novo or truncating SHANK2 mutation 1/965, 0.10%).”
From Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments (2014) · cites this paper as [32]
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 [32]
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 [32]
The published GWAS for ASD are small by current standards.
“the published GWAS for ASD are small by current standards. 86–89”
From Genetic architectures of psychiatric disorders: the emerging picture and its implications (2012) · cites this paper as [86]
Many studies of complex neuropsychiatric disorders have concluded that disease-causing variants are often clustered in protein-interaction networks with a high degree of connectivity among themselves and that these clustered networks are often enriched with functional pathways relevant to brain functions.
“Many studies of complex neuropsychiatric disorders have also concluded that disease-causing variants are often clustered in protein-interaction networks with a high degree of connectivity among themselves and that these clustered networks are often enriched with functional pathways relevant to brain functions [72–80].”
From An integrated analysis of genes and functional pathways for aggression in human and rodent models (2019) · cites this paper as [73]
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“TADA requires a mutational model (Sanders et al., 2012; Neale et al., 2012; Samocha et al., 2014) which accounts for gene size and sequence composition to obtain an expectation for mutations per gene, given sample size.”
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Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
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Self-citationHistone Acetylome-wide Association Study of Autism Spectrum Disorder
Sun, W., Poschmann, J., Cruz-Herrera del Rosario, R., Parikshak, N. N., Hajan, H. S., Kumar, V., Ramasamy, R., Belgard, T. G., Elanggovan, B., Wong, C. C. Y., et al. (2016) · Cell · doi:10.1016/j.cell.2016.10.031 · Cited by 306 · see citing works
Self-citationThe promises and challenges of human brain organoids as models of neuropsychiatric disease
Quadrato, G., Brown, J., & Arlotta, P. (2016) · Nature Medicine · doi:10.1038/nm.4214 · Cited by 304 · see citing works
Determinants of Mutation Rate Variation in the Human Germline
Ségurel, L., Wyman, M. J., & Przeworski, M. (2014) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-031714-125740 · Cited by 289 · see citing works
Getting to the cores of autism
Iakoucheva, L. M., Muotri, A. R., & Sebat, J. (2019) · Cell · doi:10.1016/j.cell.2019.07.037 · Cited by 260 · see citing works
“, 2007) and protein-altering point mutations (Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2012; Sanders et al., 2012) contribute to risk for ASD.”
BackgroundPaternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity
D’Onofrio, B. M., Rickert, M. E., Frans, E., Kuja-Halkola, R., Almqvist, C., Sjölander, A., Larsson, H., & Lichtenstein, P. (2014) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2013.4525 · Cited by 282 · see citing works
Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms
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Lim, E. T., Raychaudhuri, S., Sanders, S. J., Stevens, C., Sabo, A., MacArthur, D. G., Neale, B. M., Kirby, A., Ruderfer, D. M., Fromer, M., et al. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.029 · Cited by 266 · see citing works
Self-citationAdvanced parental age and autism risk in children: a systematic review and meta‐analysis
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- Authors
- 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., Walker, M. F., Ober, G. T., Teran, N. A., Song, Y., El-Fishawy, P., Murtha, R. C., Choi, M., Overton, J. D., Bjornson, R. D., Carriero, N. J., Meyer, K. A., Bilguvar, K., Mane, S. M., Šestan, N., Lifton, R. P., Günel, M., Roeder, K., Geschwind, D. H., Devlin, B., & State, M. W.
- Affiliations
- Yale University (US)
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Carnegie Mellon University (US)
- University of Pittsburgh (US)
- Corresponding author
- Geschwind, Daniel H.
- Devlin, Bernie
- State, Matthew W.
- ORCID
- Venue
- Nature
- Published
- 2012-04-04
- Volume
- 485
- Issue
- 7397
- Pages
- 237-241
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3667984
- OpenAlex
- W2131104106
- Semantic Scholar
- 122b231f10c7693d8adb51eacd8b5106edc50278
- Cited by
- 2,084
- References
- 24
- Citations by year
- 2026: 55 · 2025: 77 · 2024: 84 · 2023: 96 · 2022: 118 · 2021: 160 · 2020: 122 · 2019: 134 · 2018: 159 · 2017: 150 · 2016: 159 · 2015: 174 · 2014: 259 · 2013: 218 · 2012: 112
- FWCI
- 124.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- 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
- National Institute of Mental Health (K08MH087639, U01MH081896, R25MH077823)
- National Institute of General Medical Sciences (T32GM008042)
- 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
- autism spectrum disorder, de novo mutations, single nucleotide variants, nonsense mutation, splice site mutation, brain-expressed genes, SCN2A, CHD8, locus heterogeneity, copy number variation, risk alleles, gene discovery
- MeSH terms
- Alleles, Autistic Disorder, Exons, Humans, Mutation, Nerve Tissue Proteins, Sodium Channels, Codon, Nonsense, Genetic Heterogeneity, Genetic Predisposition to Disease, RNA Splice Sites, Siblings, Exome, NAV1.2 Voltage-Gated Sodium Channel
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