De Novo Gene Disruptions in Children on the Autistic Spectrum
Open accessAbstract
Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.
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- Findingown data
There is no significantly greater number of de novo missense mutations in affected children compared with unaffected siblings.
“We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children”
Quote in the paperSubstantial claim - Findingown data
A de novo mutation was found in GRM5, a target upstream of FMR1.
“As a follow-up to this striking observation, we searched for de novo mutations in targets upstream of FMR1 and found an intriguing one: GRM5.”
Quote in the paperNot a substantial claim - Findingown data
The paper found a remarkable overlap between FMRP-associated genes and their lists of 59 LGD targets and 72 most likely autism candidate genes from de novo CNVs: 14 and 13 with one in common, thus 26/129, with a p value of 10−13.
“Hence, we checked the list of FMRP-associated genes with our lists of 59 LGD targets and 72 most likely autism candidate genes from de novo CNVs, and found a remarkable overlap: 14 and 13 with one in common, thus 26/129, with a p value of 10−13 determined on a per gene basis (842 FMRP-associated genes out of 25,000 genes).”
Quote in the paperSubstantial claim - Findingown data
Using a well-annotated set of human genes as controls, FMRP-associated genes are strongly depleted for mutations that affect splicing or introduce stop codons.
“Using a well-annotated set of human genes as controls, FMRP-associated genes are strongly depleted for mutations that affect splicing or introduce stop codons.”
Quote in the paperSubstantial claim - Findingown data
The list of genes with disruptive de novo mutations in children with autism shows an unusual coincidence with the list of 842 gene products associated with FMRP.
“We observe an unusual coincidence between the list of genes with disruptive de novo mutations in children with autism and the list of 842 gene products associated with FMRP”
Quote in the paperNot a substantial claim
- Findingown data
We find almost no evidence of a role for transmission genetics.
“We find almost no evidence of a role for transmission genetics.”
Quote in the paperSubstantial claim - Findingown data
Parental age plays a role in mutation rate.
“Parental age also appears to play a role in mutation rate”
Quote in the paperSubstantial claim - Findingown data
Thirteen of the 59 LGD candidates appear to be involved in transcription regulation or chromatin remodeling.
“We also note that thirteen of the 59 LGD candidates appear to be involved in either transcription regulation or chromatin remodeling.”
Quote in the paperNot a substantial claim - Findingown data
Combining data, the p value that the overlap with FMRP-associated genes is mere coincidence is 2 × 10−4.
“Combining data, we now compute a p value of 2 × 10−4 that this is mere coincidence.”
Quote in the paperSubstantial claim - Findingown data
Only 4 of 10,000 permutations produced an overlap equal to or larger than the observed 13 FMRP-associated genes.
“Only 4 of 10,000 permutations produced an overlap equal to or larger than the observed 13 FMRP-associated genes.”
Quote in the paperSubstantial claim - Findingown data
In children on the autism spectrum, de novo mutations that disrupt genes (nonsense, splice site, and frame-shift) occur at twice the rate of their unaffected siblings, with counts of 59 and 28.
“gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28”
Quote in the paperSubstantial claim - Findingnone given
FMRP-associated genes are under greater purifying selection than the remainder of genes.
“We find FMRP-associated genes are under greater purifying selection than the remainder of genes”
Quote in the paperSubstantial claim - Findingown data
The de novo small indels and point substitutions identified in these families come mostly from the paternal line.
“which come mostly from the paternal line in an age-dependent manner”
Quote in the paperNot a substantial claim - Findingown data
Apart from NRXN1, none of the detected de novo LGD targets had been conclusively linked to ASD independent of FMR1 association.
“Other than NRXN1, we did not see any genes among the detected de novo LGD targets that had been conclusively linked to ASD (independent of FMR1 association)”
Quote in the paperSubstantial claim - Findingown data
The paternal origin of these de novo mutations is age-dependent.
“in an age-dependent manner”
Quote in the paperNot a substantial claim - Interpretationreasoning
If all G genes had a uniform probability of being a target and mutations were completely penetrant, the mean number of vulnerability genes per affected individual T equals G(A−1)/N.
“If each of G total genes had a uniform probability of being a target for a de novo mutation, and T was the mean number of vulnerability genes per affected, and mutations of the class were completely penetrant, we also have S = T / G, so T=GS=G(A−1)N.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Genes have a uniform probability of being a target for de novo mutation.
- The authors state this as an assumption: Mutations of the class are completely penetrant.
- Interpretationreasoning
The five genes that are recurrent targets of de novo disruptions in probands are almost certainly autism targets.
“With our projected differential between probands and sibling controls, these five genes that are recurrent targets of de novo disruptions in probands are almost certainly autism targets.”
Quote in the paperSubstantial claim - Interpretationreasoning
Nearly half of autism target genes are projected to be among the list of FMRP-associated genes.
“We project that nearly half of autism target genes will be among the list of FMRP-associated genes.”
Quote in the paperSubstantial claim - Interpretationown data
The paper provides evidence from a de novo 2 bp frame shift deletion that mutations in CTTNBP2 may cause ASD.
“We now provide evidence, based on a de novo 2 bp frame shift deletion, that mutations in CTTNBP2 may cause ASD.”
Quote in the paperSubstantial claim - Study design and conductnone given
The average vulnerability of individuals in a population can be estimated from the ratio of de novo LGD events in probands to those in siblings.
“The average individual vulnerability over a population can be measured from the ratio of number of de novo LGD events in probands and siblings, as follows.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The size of individual vulnerability appears to be roughly half the target size of all autism genes.
“Nevertheless we make note that the size of individual vulnerability appears to be roughly half the target size of all autism genes (see last section of the Discussion).”
Quote in the paperNot a substantial claim - Interpretationown data
Judging from the two-fold differential rate in probands and siblings, at least half of the 127 hits, about 65, are causal.
“Judging from our two-fold differential rate in probands and siblings, we expect that at least half of the 127 hits, about 65, are causal.”
Quote in the paperSubstantial claim - Interpretationreasoning
Using N = 150, A = 2, and G = 25,000 for LGD in autism, the average individual vulnerability per child is 167 genes.
“Now, for LGD in autism, taking N = 150, A = 2 and G = 25,000, we can compute the average individual vulnerability per child as 167 genes.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Genes have a uniform probability of being a target for de novo mutation.
- The authors state this as an assumption: Mutations of the class are completely penetrant.
- Interpretationreasoning
From the estimate of 65 causal gene disruptions and 5 recurrent gene targets, the total number of dosage-sensitive targets for autism is projected to be about 370 genes.
“From our estimate of 65 causal gene disruptions and 5 recurrent gene targets, we project that the total number of dosagesensitive targets for autism is about 370 genes.”
Quote in the paperSubstantial claim - Interpretationown data
Including de novo copy number variation, the types of mutation detectable contribute collectively to about 16% of cases of simplex autism.
“the types of mutation we can now detect contribute collectively to about 16% of the cases of simplex autism”
Quote in the paperSubstantial claim - Interpretationreasoning
For a given mutation class, the proportion of all de novo mutations in a population that contribute to the condition is S = (A−1)/N, where A is the rate ratio in probands versus unaffecteds and N is the inverse incidence.
“Thus the proportion of all de novo mutations in a population of size P that contribute to the condition is S=(A−1)RP/NRP=A−1N. S is the probability that a de novo mutation of the particular class will contribute to the condition, and S is a function only of AandN.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The rate for a given mutation class in unaffecteds is R and in probands is AR.
- Interpretationreasoning
Based on the differential and the number of recurrent and total targets of gene disruption, there are between 350 and 400 autism susceptibility genes.
“we estimate between 350 and 400 autism susceptibility genes”
Quote in the paperSubstantial claim - Interpretationreasoning
The de novo events reported are largely and perhaps almost entirely germline in origin.
“the de novo events we report are largely and perhaps almost entirely germline in origin”
Quote in the paperSubstantial claim- The authors state this as an assumption: After zygote formation, the mother's and father's genomes are equally vulnerable to subsequent somatic mutation.
- Interpretationreasoning
The number of genes whose disruption would cause a disorder in a given person is not the same as the total target size for autism, since it varies with genetic background and future events.
“The size of individual vulnerability is not the same as the target size of autism genes because the former depends on genetic background and future history.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The RIMS1 frame shift allele found in the study may lead to a condition as severe as that seen in mice with a targeted Rims1 mutation.
“and the frame shift allele we found may lead to a similarly severe condition.”
Quote in the paperNot a substantial claim - Interpretationreasoning
This study shows that these components may be dosage-sensitive targets in autism.
“This study shows these components may be dosage-sensitive targets in autism.”
Quote in the paperSubstantial claim - Study design and conductown data
This study lacks statistical power to reject the hypothesis that missense or synonymous mutations make a major contribution.
“this study lacks the statistical power to reject the hypothesis that missense or synonymous mutations make a major contribution”
Quote in the paperSubstantial claim - Interpretationreasoning
The difference in depletion may reflect strong purifying selection in humans against disruptions of even a single allele of genes in this set.
“This difference may reflect the strong purifying selection in humans against disruptions of even a single allele of genes in this set.”
Quote in the paperNot a substantial claim - Interpretationcitation
FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2.
“FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2 (Darnell et al., 2011; Auerbach et al., 2011).”
Quote in the paperNot a substantial claim0 of 2 sources checked
- May combine two claims. 17
- The quote only partly states this claim. 2
- Classified as probably not a substantial claim. 11
May combine two claims.
Findingown dataThe father is more frequently the parent of origin than the mother: 50/17 for SNVs and 6/1 for indels, combined p=10−5.
“We found that the father is more frequently the parent of origin than the mother: 50/17 for SNVs and 6/1 for indels”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFive genes were hit twice, and DYRK1A and POGZ are new recurrences found by combining the current data with the three studies.
“Five genes were hit twice. DYRK1A and POGZ are the new recurrences found by combining our data with theirs.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA similar depletion of LGDs is seen in human orthologs of mouse genes enriched for essential genes, but not in a set of 250 genes linked to known disabling genetic disorders.
“We see a similar depletion of LGDs in a set of human orthologs of mouse genes that are enriched for essential genes but we do not see this extreme depletion in a set of 250 genes linked to known disabling genetic disorders.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
FindingreasoningWith the 59 from this study, a total of 127 de novo gene disruption hits in probands have been found across the four studies.
“With the 59 from this study, a total of 127 hits in probands have been found.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Findingnone givenASH1L, KDM6B, and MLL5 are also FMRP-associated genes.
“These three are also FMRP-associated genes.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThere was no unusual overlap between FMRP-associated genes and de novo LGD targets in unaffected siblings, or between FMRP-associated genes and de novo missense targets in either affected or unaffected children.
“We found no unusual overlap between the FMRP-associated genes and de novo LGD targets in unaffected siblings, or between FMRP-associated genes and de novo missense targets in either affected or unaffected children.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFifteen of the 68 gene disruptions in the other studies hit FMRP-associated genes, a rate similar to the 14 of 59 observed in this study.
“However, 15 of their 68 do hit these genes, a rate similar to what we observed (14 of 59).”
Quote in the paperSubstantial claimMay combine two claims.
Findingnone givenThe GRM5 mutation is a deletion that is not a frame shift but removes a single amino acid and causes an additional substitution at the deletion site.
“It is hit by a deletion that is not a frame shift but removes a single amino acid and causes an additional substitution at the deletion site.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA targeted Rims1 mutation in the mouse leads to increased postsynaptic density and impaired associative learning, memory, and cognition.
“A targeted Rims1 mutation in the mouse leads to increased postsynaptic density and impaired associative learning as well as memory and cognition deficits (Powell et al., 2004; Schoch et al., 2002)”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningChildren do not necessarily share the same set of genes whose disruption would cause the disorder.
“Children do not necessarily have the same set of vulnerability genes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningThe estimate of 167 vulnerability genes is crude because genes do not have a uniform mutation rate and not every LGD in a target gene is completely penetrant.
“This of course is only a crude argument because genes do not have a uniform mutation rate, and not every LGD in a target gene will have complete penetrance.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenFor indel calls, the study used relaxed denovoScr and pEχ2 requirements to 30 and 10−9 but required clean counts: parents had no reads with the candidate indel and at least 15 reads supporting the reference allele; at least one child had 6 or more reads with the candidate allele comprising at least 5% of her reads.
“For the “Indel filter,” we substantially relaxed the denovoScr and pEχ2 requirements to 30 and 10−9 but insisted on having clean counts: parents were not allowed to have any reads with the candidate indel and were required to have at least 15 reads supporting the reference allele. At least one of the children had to have 6 or more reads with the candidate allele comprising at least 5% of her reads”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe study used filter thresholds of denvoScr >= 60 and pEχ2 >= 0.0001 for de novo SNV candidates.
“We only considered de novo candidates with denvoScr > = 60 and pEχ2>=0.0001.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenCandidate de novo variants were confirmed via a PCR and pooled high-throughput sequencing procedure.
“Candidate de novo variants were confirmed via a PCR and pooled highthroughput sequencing procedure.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningBy extension, neuroplasticity might have a general vulnerability to mutation affecting gene dosage.
“By extension, neuroplasticity, the hallmark function of our nervous system that enables learning and adaption in responses to stimulation, might have a general vulnerability to mutation affecting gene dosage.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningIt is reasonable to suppose that the physiological mechanisms modulated by FMRP depend on protein concentration, which might be sensitive to gene dosage.
“Hence, it is reasonable to suppose that the physiological mechanisms modulated by FMRP depend on protein concentration, which in turn might be sensitive to gene dosage.”
Quote in the paperSubstantial claim- Rests on an assumption: FMRP inhibits translation of critical transcripts involved in neuroplasticity.
May combine two claims.
Interpretationnone givenThe overlap is remarkable because half of the LGD targets should not be ASD related, and probably a similar number of the most likely CNV genes.
“This overlap is remarkable because half of the LGD targets should not be ASD related, and probably a similar number of the most likely CNV genes.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningWith this target size and an expected 50% increase in rate of discovery of de novo gene disruptions, similar studies of all 2800 SSC families should yield about 116 autism genes, identifying about a third of the dosage-sensitive gene targets.
“With this target size, and an expected 50% increase in rate of discovery of de novo gene disruptions, similar studies of all 2800 SSC families should yield about 116 autism genes, thereby identifying unequivocally about a third of the dosage-sensitive gene targets.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown dataOf 357 families, 343 met coverage targets and passed gender, pedigree, and sample integrity checks, and only those 343 were considered in this report.
“Three hundred forty-three families met coverage targets and passed gender, pedigree, and sample integrity checks. Only those 343 families were considered in this report.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe institutional review board of Cold Spring Harbor Laboratory approved this study, and written informed consent from all subjects was obtained by SFARI.
“The institutional review board of Cold Spring Harbor Laboratory approved this study, and written informed consent from all subjects was obtained by SFARI.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationA set of 842 FMRP-associated genes has been enumerated by HITS-CLIP, and this set was previously noted to overlap candidate genes from de novo CNVs.
“A set of 842 FMRP-associated genes has been enumerated by cross-linking, immunoprecipitation, and high-throughput sequencing (HITS-CLIP), and this set was previously noted to overlap candidate genes from de novo CNVs (Darnell et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Darnell et al., 2011 source
Not checked in the free run.
May combine two claims. The quote only partly states this claim.
Study design and conductown dataThe expectation of number of variants per gene was based on the distribution of observed rare synonymous mutations in the 686 parents; 7,051 of 63,080 (11.18%) of all rare synonymous SNVs fell within FMRP-associated genes.
“Specifically, 7,051 of the 63,080 (or 11.18%) of all rare synonymous SNVs fell within the FMRP-associated genes (Table 6).”
Quote in the paperSubstantial claim
The authors state this as an assumption.
After zygote formation, the mother's and father's genomes are equally vulnerable to subsequent somatic mutation.
“We infer this by assuming that after zygote formation, the mother’s and father’s genomes are equally vulnerable to subsequent somatic mutation.”
The authors state this as an assumption.
Genes have a uniform probability of being a target for de novo mutation.
“If each of G total genes had a uniform probability of being a target for a de novo mutation”
The authors state this as an assumption.
Mutations of the class are completely penetrant.
“and mutations of the class were completely penetrant”
The authors state this as an assumption.
SNV and indel variants occur randomly across coding regions.
“Under the assumption that SNV and indel variants occur randomly across coding regions”
The paper relies on this without support.
Fragile X syndrome is a common genetic cause of intellectual disability and many affected children have autistic symptoms.
“Fragile X syndrome (FXS) is one of the most common genetic causes of intellectual disability, with up to 90% of affected children exhibiting autistic symptoms.”
The paper relies on this without support.
FMR1 is expressed in neurons and controls translation of many products.
“The FMR1 gene is expressed in neurons and controls the translation of many products.”
The paper relies on this without support.
FMRP inhibits translation of critical transcripts involved in neuroplasticity.
“FMRP has been proposed to inhibit protein translation of certain critical transcripts involved in neuroplasticity, the coordinated sensitization or desensitization of neurons in response to activity.”
The authors state this as an assumption.
The allele in a read may be incorrectly called once per hundred times, independent for family member and position.
“In our computations, we use a simple error model in which the allele in a read may be incorrectly called once per hundred times, and is assumed independent for family member and position.”
The authors state this as an assumption.
The rate for a given mutation class in unaffecteds is R and in probands is AR.
“Assume the rate for a given mutation class in unaffecteds is R, and the rate in probands is AR.”
The authors state this as an assumption.
The genotypes follow a two allele standard autosomal model.
“The genotypes are assigned based on the likelihood of the 81 possible states given a two allele standard autosomal model”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NCKAP1 and eIF4E have been shown to be genetically associated with autism spectrum disorder.
“the two key CYFIP1 interactors examined here, NCKAP1 and eIF4E, have been shown to be genetically associated with ASD (Iossifov et al., 2012, Neves-Pereira et al., 2009).”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Iossifov et al., 2012
The Discussion’s “Candidate Genes” section (page not supplied) discusses ASD-linked mutations in other genes but does not identify NCKAP1 or eIF4E. Searches for NCKAP1, eIF4E, and their association with autism found no passage in our copy addressing the claimed associations. (LLM, conf=0.73)
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 [37]
In Text S1 we show, using Jensen's Inequality, that the non-uniform distribution of the mutation rates and the relative risks among the ASD risk genes leads to a significant under-estimation of , explaining the discrepancy between our results and those of Iossifov et al.
“In Text S1 we show, using Jensen's Inequality, that the non-uniform distribution of the mutation rates and the relative risks among the ASD risk genes leads to a significant under-estimation of , explaining the discrepancy between our results and those of Iossifov et al. [4].”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [4]
In a recent paper using the same de novo data, the number of ASD risk genes was estimated at 370.
“In a recent paper using the same de novo data, the number of ASD risk genes () was estimated at 370 [4].”
From Integrated Model of De Novo and Inherited Genetic Variants Yields Greater Power to Identify Risk Genes (2013) · cites this paper as [4]
Exome sequencing has found de novo single nucleotide variations and indels that segregate with ASD.
“Exome sequencing has uncovered de novo single nucleotide variations (SNVs) and insertion/deletion (indel) mutations that segregate with ASD.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Iossifov 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 Iossifov et al., 2012
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 Iossifov et al., 2012
De novo structural variants and protein-altering point mutations contribute to ASD risk.
“Early studies established that de novo structural variants (SVs) (Brandler et al., 2016; Sebat et al., 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.”
From Getting to the cores of autism (2019) · cites this paper as Iossifov 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 [7]
Iossifov and colleagues reported an enrichment of ASD RDNVs in FMRP targets.
“Similarly, Iossifov and colleagues reported an enrichment of ASD RDNVs in FMRP targets5.”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [5]
The I-exomes list comprises 59 genes disrupted by de novo nonsense, frameshift or splice-site point mutations in autism probands from Iossifov et al.
“(vi) Steinberg et al.36 compiled a list of genes disrupted by de novo nonsense, frameshift or splice-site point mutations in autism probands that were obtained from Iossifov et al.5 (59 genes; referred to as ‘I-exomes’)”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [5]
Many FMRP targets are highly conserved and under purifying selection.
“As many FMRP targets are highly conserved and are under purifying selection72,87,117”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [72]
RNA targets of FMRP identified by CLIP-seq are highly enriched for de novo mutations in autism spectrum disorder.
“Using CLIP–seq, investigators identified the RNA binding targets of the translational regulator fragile X mental retardation protein (FMRP)116, and a subsequent analysis found that these targets are highly enriched for de novo mutations in ASD72.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [72]
CHD8 is the gene most frequently affected by ASD-associated rare de novo variation.
“chromodomain helicase DNA-binding protein 8 (CHD8)118, which is the gene most frequently affected by ASD-associated rare de novo variation72,119–121.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [72]
Whole genome sequencing has identified a list of candidate genes in ASD.
“Recently, whole genome sequencing technology has successfully identified a list of candidate genes in ASD (Bi et al., 2012; Chahrour et al., 2012; Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2012a; Sanders et al., 2012)”
From Modeling Autism by SHANK Gene Mutations in Mice (2013) · cites this paper as Iossifov et al., 2012
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 [26]
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 [26]
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 [26]
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 [26]
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 [26]
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 [26]
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 [26]
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 [26]
Disruptive de novo mutations in ASH1L, KDM6B, and MLL5 suggest that chromatin remodeling activity of these proteins may be an underlying pathway in ASD and ID.
“Additional disruptive de novo mutations recognized in ASH1L [ash1 (absent, small, or homeotic)-like (Drosophila)], KDM6B [lysine (K)-specific demethylase 6B], and MLL5 [myeloid/lymphoid or mixed-lineage leukemia 5 (trithorax homolog, Drosophila)] suggest that the chromatin remodeling activity of these proteins may be an underlying pathway implicated in ASD and ID [26].”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [26]
Whole-exome sequencing of large ASD cohorts has expanded the set of known ASD-linked genes beyond those found by traditional genetic approaches and targeted sequencing.
“Recent whole-exome sequencing analyses of large ASD cohorts (21)(22)(23)(24)(25)(26)(27)(28)(29) have expanded the repertoire of known genes harboring ASD-linked mutations that were previously identifiable only by traditional genetic approaches and targeted sequencing (14,15).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [23]
Rare genetic risk variants identified so far have a very large effect on individual ASD risk.
“Rare genetic risk variation identified to date, in contrast, has a very substantial effect on individual risk.Recent whole-exome sequencing analyses of large ASD cohorts (21)(22)(23)(24)(25)(26)(27)(28)(29) have expanded the repertoire of known genes harboring ASD-linked mutations”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [23]
More than 50 high-risk ASD genes have emerged from large-scale sequencing studies, most under an autosomal dominant model.
“To date, in addition to causal and highly penetrant genes and genomic loci identified before whole-exome sequencing (15,30), over 50 high-risk genes have emerged from the large-scale sequencing studies (21)(22)(23)(24)(25)(26), most under a model of autosomal dominant variation.”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [23]
CHD2 has been associated with ASD, intellectual disability, epilepsy, and photosensitivity.
“CHD2 has been associated with ASD (22,23), ID (73), epilepsy (82,87) and photosensitivity (83).”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [23]
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 [15]
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 [166]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Synonymous-variant proportion is stated as a percentage without the percent sign
MinorThe proportion is about 0.1118; 11.18 is its percentage value. Elsewhere the paper correctly labels this value 11.18%.
Reported 11.18 · recomputed 0.111779
“We observed 63,080 synonymous rare variants with 7,051 falling within FMRP-associated genes, a proportion of 11.18.”
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- Authors
- Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y.-H., Narzisi, G., Leotta, A., Kendall, J., Grabowska, E., Ma, B., Marks, S., Rodgers, L., Stepansky, A., Troge, J., Andrews, P., Bekritsky, M., Pradhan, K., Ghiban, E., Kramer, M., Parla, J., Demeter, R., Fulton, L. L., Fulton, R. S., Magrini, V. J., Ye, K., Darnell, J. C., Darnell, R. B., Mardis, E. R., Wilson, R. K., Schatz, M. C., McCombie, W. R., & Wigler, M.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- Washington University in St. Louis (US)
- Albert Einstein College of Medicine (US)
- Rockefeller University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wigler, Michael
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 74
- Issue
- 2
- Pages
- 285-299
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3619976
- OpenAlex
- W2085198610
- Cited by
- 1,446
- References
- 44
- Citations by year
- 2026: 31 · 2025: 50 · 2024: 64 · 2023: 61 · 2022: 72 · 2021: 91 · 2020: 90 · 2019: 117 · 2018: 103 · 2017: 137 · 2016: 119 · 2015: 143 · 2014: 188 · 2013: 128 · 2012: 48
- FWCI
- 90.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- Simons Foundation
- Simons Foundation Autism Research Initiative
- National Institutes of Health (5rc2mh090028-02)
- National Institute of Mental Health (RC2 MH090028, 5RC2MH090028-02)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD040647)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, de novo mutations, gene disruption, nonsense mutation, splice site mutation, frameshift mutation, paternal age, autism susceptibility genes, FMRP, synaptic plasticity, purifying selection, dosage sensitivity, exome sequencing
- MeSH terms
- Child, Child Development Disorders, Pervasive, Child, Preschool, Family Health, Female, Humans, Male, Models, Molecular, Mutation, Parents, Phenotype, Gene Dosage, Genetic Predisposition to Disease, Fragile X Messenger Ribonucleoprotein 1, Genetic Association Studies
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