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Cited by 998Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Open access
Pinto, Dalila, Delaby, Elsa, Merico, Daniele, Barbosa, Mafalda, Merikangas, Alison, Klei, Lambertus, Thiruvahindrapuram, Bhooma, Xu, Xiao +104 more·2014·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2014.03.018PMC PMC4067558
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Abstract

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

AI snapshot

Written from the paper’s full text.

TL;DR

This study analyzed rare copy-number variation (CNV) in 2,446 autism spectrum disorder (ASD)-affected families and 2,640 controls, confirming excess genic CNV burden and enrichment of pathogenic CNVs at ASD/intellectual disability loci. Genes affected by de novo CNVs and loss-of-function single-nucleotide variants converged on neuronal signaling, synapse, and chromatin-regulation networks.

Key findings

  • Affected subjects showed a 1.41-fold increase in genes affected by rare CNVs versus controls (empirical p = 1 × 10−5). Pathogenic CNVs overlapping autosomal-dominant or X-linked ASD/ID genes and loci were found in 2.8% (60/2,147) of European-ancestry affected subjects (OR = 12.62, 95% CI = 5.44–29.27, p = 2.74 × 10−15); across all ancestries, pathogenic CNVs were identified in ∼3.3% (82/2,446).
  • Among 2,096 trios, 102 rare de novo CNVs were found in 99 affected subjects, with 4.7% of trios having at least one de novo CNV. De novo events averaged 1.17 Mb versus 0.67 Mb in unaffected siblings (p = 0.01) and 0.55 Mb in control trios (p = 0.01), and affected 3.8-fold more genes than control de novo CNVs.
  • Females were more likely to carry highly penetrant pathogenic CNVs (male-to-female ratio 2:1 versus 6:1 among all affected subjects; p = 0.017) and were overrepresented among subjects with exonic deletions overlapping FMRP targets (17 females in 73 affected subjects, 1.98-fold more than males, p = 0.022).
  • Network analyses linked de novo CNVs and de novo LoF SNVs to neuronal signaling and development, synapse function, and chromatin regulation: a NETBAG network of 113 genes (global cluster p = 0.02) and a DAPPLE protein-protein interaction network of 151 genes with 1.5-fold more direct interactions than expected (p < 0.001).

Methods

  • The Autism Genome Project sample included 2,446 ASD-affected families passing QC (from 2,845 families and 9,050 individuals) and 2,640 unrelated European-ancestry controls; all were genotyped on Illumina 1M arrays and analyzed with the same QC and CNV pipeline.
  • CNV burden was compared between affected subjects and controls with Fisher’s exact tests, PLINK, R, and custom scripts; de novo and clinically relevant CNVs were validated by quantitative PCR, MLPA, and/or long-range PCR.
  • Analyses included gene-list burden tests (ASD/ID loci, BrainSpan brain-expressed genes, postsynaptic density genes, FMRP targets, HPO/MPO neurological genes, haploinsufficiency probability), logit models for multigene burden, and functional enrichment/network analyses using NETBAG and DAPPLE.

Limitations

  • The paper states that many subjects were assessed with clinical diagnostic methods and excluded if positive, and individuals with known congenital malformations or dysmorphic features were not enrolled, so the etiologic yield is likely an underestimate.
  • The paper notes that some CNVs were seen in a small fraction of controls, consistent with variable expressivity and/or incomplete penetrance.
  • Evident from the text: main analyses were restricted to European-ancestry subjects, and CNV detection relied on array-based calls rather than sequence data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ajhg.2014.03.018

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 61 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Even after controlling for the difference in CNV size by proportionally scaling the number of intersected genes in each group, there was a 1.77-fold difference (1.2-fold for deletions and 2.8-fold for duplications, p = 0.02).

    “Even after controlling for the difference in CNV size by proportionally scaling the number of intersected genes in each group, we observed a 1.77-fold difference (1.2-fold for deletions and 2.8-fold for duplications, p = 0.02).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The published control de novo CNV datasets (unaffected siblings from the Simons Simplex Collection and Icelandic control trios) are comparable to the AGP affected subjects for CNV size and gene-content comparisons.
  • Findingown data

    FMRP targets (n = 842) and PSD genes (n = 1,453) carried a significant excess of both deletions and duplications in affected subjects.

    “FMRP targets (n = 842) and PSD genes (n = 1,453) carried a significant excess of both deletions and duplications in affected subjects (Figures 3A and 3B).”
    Quote in the paperSubstantial claim
  • Findingown data

    The proportion of females was significantly increased among carriers of highly penetrant pathogenic CNVs (male-to-female ratio of 2:1 versus 6:1 among all affected subjects; two-tailed Fisher's exact test p = 0.017).

    “We also observed that the proportion of females was significantly increased among carriers of highly penetrant pathogenic CNVs (male-to-female ratio of 2:1 versus 6:1 among all affected subjects; two-tailed Fisher’s exact test p = 0.017; Figure 2E).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The male-to-female ratio among individuals with CNVs associated with variable expressivity was 6:1.

    “In contrast, the male-to-female ratio among individuals with CNVs associated with variable expressivity was 6:1.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The rare CNV gene burden enrichment remained after controlling for potential case-control differences.

    “This enrichment was apparent for both deletions and duplications and remained after we controlled for potential case-control differences (Table 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Unrelated control subjects from SAGE, the Ontario Colorectal Cancer Case-Control Study, and HABC, who had no obvious psychiatric history, are valid controls for ASD CNV burden analyses.
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Findingown data

    Two unrelated males harbored Xq28 duplications, one de novo and one maternal, corresponding to a ∼0.3 Mb segmental-duplication-mediated gain (153.2-153.5 Mb), previously reported in X-linked ID.

    “For example, two unrelated males were found to harbor Xq28 duplications (MIM 300815), one de novo and one maternal, corresponding to a ∼0.3 Mb segmental-duplication-mediated gain (153.2–153.5 Mb), which was previously reported in X-linked ID.42”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Vandewalle, 2009, Dosage-dependent severity of the phenotype in patients with mental retardation due to a recurrent copy-number gain at Xq28 mediated by an unusual recombination, Am. J. Hum. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The majority of 15q11-q13 duplications were of maternal origin, but two were paternally derived.

    “The majority of these duplications were of maternal origin, but two were paternally derived (one without information; Table S9).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The excess of affected subjects carrying deletions overlapping PSD genes was independent of the signal in FMRP targets (OR = 2.62, 95% CI = 1.62-4.32, p = 2.24 × 10−5) and represented 4% of subjects with exonic events (59/1,486) or 3% after exclusion of pathogenic events (p = 0.007).

    “Given that the lists of FMRP targets and PSD genes shared 279 genes, we performed conditional analyses showing that the excess of affected subjects carrying deletions overlapping PSD genes was independent of the signal in FMRP targets (OR = 2.62, 95% CI = 1.62–4.32, p = 2.24 × 10−5) and represented 4% of subjects with exonic events (59/1,486) or 3% after exclusion of pathogenic events (p = 0.007).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among 102 de novo CNVs identified, half (n = 46) are considered etiologically relevant, including 40 loci known to be involved in ASD and ID.

    “The clinical relevance of de novo CNVs in ASD is confirmed by the fact that among 102 such events identified, half (n = 46) are considered etiologically relevant, including 40 loci known to be involved in ASD and ID (see below).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Five percent (73/1,486) of affected subjects with exonic CNVs, including 52 subjects with genes not previously implicated in ASD and/or ID, carried deletions overlapping one or more FMRP targets, yielding 43 ASD candidate genes.

    “Five percent (73/1,486) of affected subjects with exonic CNVs, including 52 subjects with genes not previously implicated in ASD and/or ID, carried deletions overlapping one or more FMRP targets, yielding 43 ASD candidate genes (Figure 3A; Table S10).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    One AGP proband with the Xq28 duplication had autism and a normal IQ, whereas the second had a borderline IQ (72).

    “Interestingly, one AGP proband with the duplication had autism and a normal IQ, whereas the second had a borderline IQ (72) (see Table S8 for phenotype information of all affected subjects with pathogenic CNVs).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    De novo CNVs affected 3.8-fold more genes in affected subjects than in control subjects (2.6-fold for deletions and 6.1-fold for duplications).

    “De novo CNVs affected 3.8-fold more genes in affected subjects than in control subjects4,31 (2.6-fold for deletions and 6.1-fold for duplications).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Sanders, 2011, Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism, Neuron source

      Not checked in the free run.

    • cites [31] Kirov, 2012, De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia, Mol. Psychiatry source

      Not checked in the free run.

    • Rests on an assumption: The published control de novo CNV datasets (unaffected siblings from the Simons Simplex Collection and Icelandic control trios) are comparable to the AGP affected subjects for CNV size and gene-content comparisons.

  • May combine two claims.

    Findingown data

    4% (87/2,147) of ASD-affected subjects had CNVs overlapping autosomal-dominant or X-linked genes and loci implicated in ASD and/or ID, significantly higher than controls (OR = 4.09, 95% CI = 2.64-6.32, p = 5.7 × 10−12).

    “When we analyzed samples of inferred European ancestry, we found that 4% (87/2,147) of ASD-affected subjects had CNVs overlapping autosomal-dominant or X-linked genes and loci implicated in ASD and/or ID; this percentage was significantly higher than that in controls (OR = 4.09, 95% confidence interval [CI] = 2.64–6.32, p = 5.7 × 10−12; Figure 1A).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Unrelated control subjects from SAGE, the Ontario Colorectal Cancer Case-Control Study, and HABC, who had no obvious psychiatric history, are valid controls for ASD CNV burden analyses.

  • May combine two claims.

    Findingown data

    64% (54/84) of pathogenic CNVs were de novo events (59% were deletions, and 41% were duplications) and the remaining 36% were inherited, including seven X-linked CNVs maternally transmitted to males and 23 on autosomes.

    “Inheritance data showed that 64% (54/84) of pathogenic CNVs were de novo events (59% were deletions, and 41% were duplications) and that the remaining (36%) were inherited, including seven X-linked CNVs maternally transmitted to males and 23 (13 maternal and 10 paternal [27%]) on autosomes (Figure 2C).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    For 85 of 102 de novo events, it was possible to determine the parent of origin, and roughly equal numbers originated on the paternal allele (n = 45) and the maternal allele (n = 40).

    “For 85 of 102 de novo events, it was possible to determine the parent of origin, and roughly equal numbers of events originated on the paternal allele (n = 45) and the maternal allele (n = 40) (Tables S5A–S5H).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our data show an increased proportion of females among carriers of highly penetrant pathogenic CNVs, as well as among carriers of deletions affecting FMRP targets.

    “(4) show an increased proportion of females among carriers of highly penetrant pathogenic CNVs, as well as among carriers of deletions affecting FMRP targets;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DAPPLE analysis of the union set of 336 unique genes resulted in a network of direct PPIs encoded by 151 genes, with 54/92 (58.7%) ASD genes, 64/113 (56.6%) de novo CNV genes, and 41/122 (33.6%) de novo LoF SNV genes.

    “The union set of 336 unique genes (Table S15) analyzed by DAPPLE37 resulted in a network of direct PPIs encoded by 151 genes (Figure 5A) from each of the three main lists: 54/92 (58.7%) genes involved in ASD, 64/113 (56.6%) de novo CNV genes, and 41/122 (33.6%) de novo LoF SNV genes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Rossin, 2011, Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology, PLoS Genet. source

      Not checked in the free run.

    • The authors state this as an assumption: Different genes harboring suspected causative mutations for the same disorder often physically interact.

  • May combine two claims.

    Findingown data

    The newly selected 97 genes have high functional-indispensability scores and a comparable high degree of centrality and number of networks in which they are involved.

    “Furthermore, similar to genes with known disease-causing mutations (Figure 6C), those genes have high functional-indispensability scores and a comparable high degree of centrality (i.e., high number of direct neighbors) and number of networks in which they are involved (Figures 6D and 6E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    De novo deletions (52 in European affected subjects) were significantly enriched within each gene set or pathway cluster (85 of 86) and across clusters (chi-square p = 9.8 × 10−9).

    “De novo deletions (52 in European affected subjects) were found to be significantly enriched within each gene set or pathway cluster (for 85 of the 86 gene sets or pathways), as well as across clusters (chi-square test p = 9.8 × 10−9) (Table S12B)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared to all other genes within de novo CNVs (or deletion CNVs only), genes in the network exhibited a significantly higher pHI (p = 7.07 × 10−8), and 55% (59/107) had pHI > 0.35.

    “Compared to all other genes within de novo CNVs (or deletion CNVs only), genes in the network exhibited a significantly higher pHI (Wilcoxon rank sum p = 7.07 × 10−8), and 55% (59/107 [6 without information]) had a pHI > 0.35.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Our findings implicate many ASD candidate genes altered by de novo, inherited, or X-linked CNVs or altered by both de novo CNVs and LoF SNVs.

    “Our findings implicate many ASD candidate genes altered by de novo, inherited, or X-linked CNVs (e.g., SETD5, miR137, and HDAC9 [MIM 606543]; Supplemental Data section “Highlighted Genes”) or altered by both de novo CNVs and LoF SNVs (e.g., RIMS1, TRIP12, and DLL1; Figures 4B and 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Eleven genes affected by de novo CNVs were found to be altered by de novo LoF SNVs among autism cohorts, and three of them (NRXN1, SHANK2, and RIMS1) were selected by NETBAG.

    “Eleven genes affected by de novo CNVs (NRXN1, SHANK2, ARID1B, RIMS1 [MIM 606629], TRIP12, SMARCC2 [MIM 601734], DLL1 [MIM 606582], TM4SF19, MLL3 [MIM 606833], PHF2 [MIM 604351], and CSTF2T [MIM 611968]) were found to be altered by de novo LoF SNVs among autism cohorts, and three of them (NRXN1, SHANK2, and RIMS1) were selected by NETBAG (Figure 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among highly penetrant pathogenic CNVs, there is a 2:1 male-to-female ratio, deviating from the overall ratio of 6:1 in the study sample.

    “Importantly, when considering highly penetrant pathogenic CNVs, we found a 2:1 male-to-female ratio (deviating from the overall ratio of 6:1 in the study sample).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The ASD-affected brother carries the same CHD2 deletion, which removes the first six exons of CHD2.

    “His ASD-affected brother has mild ID, similar dysmorphic features, and epilepsy with onset at age 9 years and carries the same deletion, which removes the first six exons of CHD2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared to the genome average, the newly selected 97 genes are among the top 75% of more-conserved genes and are highly expressed in the brain.

    “Compared to the genome average, they are also among the top 75% of more-conserved genes (on the basis of Genomic Evolutionary Rate Profiling scores and PhyloP) and are highly expressed in the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our data confirm the contribution of de novo CNVs to the etiology of autism and highlight the contribution of inherited pathogenic imbalances (36%).

    “(3) confirm the contribution of de novo CNVs to the etiology of autism and highlight the contribution of inherited pathogenic imbalances (36%);”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    These findings are consistent among the three different types of analyses shown in Figures 4A, 4B, and 5.

    “Overall, these findings are consistent among the three different types of analyses shown in Figures 4A, 4B, and 5.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingreasoning

    The CHD2 deletion arose on the paternal chromosome.

    “(the deletion arose on the paternal chromosome)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Our data show that both deletions and duplications involving FMRP targets and PSD genes increase ASD risk.

    “(6) show that both deletions and duplications involving FMRP targets and PSD genes increase ASD risk;”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    39 of the 97 genes are either FMRP-related or PSD genes; of the initial 151 genes identified by DAPPLE, 51 are FMRP interactors and 24 are PSD genes.

    “Interestingly, 39 of the 97 genes are either FMRP-related or PSD genes (of the initial 151 genes identified by DAPPLE, 51 are FMRP interactors and 24 are PSD genes).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The gene-set analysis results were recapitulated, notably for synapse functions and processes, and genes involved in chromatin and transcription regulation were also identified.

    “We recapitulated many of the results of our gene-set analysis (Figure 4A), notably for synapse functions and processes, and also identified genes involved in chromatin and transcription regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Enrichment of synaptic functioning has also been reported among inherited events in the AGRE families and among de novo events in the Simons Simplex Collection.

    “Enrichment of synaptic functioning has also been reported among inherited events in the AGRE families47 and among de novo events in the Simons Simplex Collection.36”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47] Gai, 2012, Rare structural variation of synapse and neurotransmission genes in autism, Mol. Psychiatry source

      Not checked in the free run.

    • cites [36] Gilman, 2011, Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses, Neuron source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Microdeletions of miR137 have been reported in ASD, ID, and schizophrenia.

    “Microdeletions of miR137 have been reported in ASD,39 ID,40 and schizophrenia.41”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [39] Carter, 2011, Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder, Clin. Genet. source

      Not checked in the free run.

    • cites [40] Willemsen, 2011, Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability, J. Med. Genet. source

      Not checked in the free run.

    • cites [41] 2011, Genome-wide association study identifies five new schizophrenia loci, Nat. Genet. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Many of the genes implicated in dominant diseases have been related to loss of function or haploinsufficiency, previously suggested to be more frequent and penetrant when deletions rather than duplications are involved.

    “Many of the genes implicated in dominant diseases have been related to loss of function or haploinsufficiency, previously suggested to be more frequent and penetrant when deletions rather than duplications are involved.46”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Turner, 2008, Germline rates of de novo meiotic deletions and duplications causing several genomic disorders, Nat. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    It is likely that de novo and pathogenic CNVs contribute to risk by altering the expression of more than one gene, suggesting that genetic interactions between these genes can underlie ASD risk.

    “Thus, it is likely that de novo and pathogenic CNVs contribute to risk by altering the expression of more than one gene, suggesting that genetic interactions between these genes can underlie ASD risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The signal further decreased 2-fold when the remaining pathogenic CNVs were removed, confirming that pathogenic inherited CNVs alone also carry risk.

    “Notably, the signal further decreased 2-fold when the remaining pathogenic CNVs were removed, confirming that pathogenic inherited CNVs alone also carry risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    At least 124 genes and 55 genomic loci have been implicated in ASD to date, all of which have also been implicated in ID.

    “At least 124 genes and 55 genomic loci have been implicated in ASD to date (Tables S6A and S6B; updated from Betancur18), all of which have also been implicated in ID.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Betancur, 2011, Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting, Brain Res. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    CNV testing and exome sequencing have so far yielded mostly nonoverlapping genes, which might reflect different mutational mechanisms, although they might still perturb connected biological pathways.

    “Interestingly, CNV testing and exome sequencing have so far yielded mostly nonoverlapping genes, which might reflect different mutational mechanisms, although they might still perturb connected biological pathways.17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Devlin, 2012, Genetic architecture in autism spectrum disorder, Curr. Opin. Genet. Dev. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Neither parent carries the CHD2 deletion, suggesting germline mosaicism.

    “Neither parent carries the deletion, suggesting germline mosaicism (the deletion arose on the paternal chromosome).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FMRP targets belong to multiple signaling and interconnected pathways such as PI3K-Akt-TSC-PTEN-mTOR and PI3K-RAS-MAPK, which have been linked to ASD through both underexpression and overexpression of genes in these pathways.

    “This is consistent with evidence that FMRP targets belong to multiple signaling and interconnected pathways such as PI3K-Akt-TSC-PTEN-mTOR and PI3K-RAS-MAPK,59,60 which have been linked to ASD through both underexpression and overexpression of genes in these pathways.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Ascano, 2012, FMRP targets distinct mRNA sequence elements to regulate protein expression, Nature source

      Not checked in the free run.

    • cites [60] Darnell, 2011, Defects in translational regulation contributing to human cognitive and behavioral disease, Curr. Opin. Genet. Dev. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The same phenomenon (female protective effect) has recently been shown for SHANK1 and the 16p13.11 CNV.

    “This same phenomenon has recently been shown for SHANK157 and the 16p13.11 CNV.58”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Sato, 2012, SHANK1 deletions in males with autism spectrum disorder, Am. J. Hum. Genet. source

      Not checked in the free run.

    • cites [58] Tropeano, 2013, Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders, PLoS ONE source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CHD2, SYNGAP1, and SYNCRIP are also affected by LoF de novo SNVs in ID, and SYNGAP1 and DPYD are altered in schizophrenia.

    “Three other genes affected by de novo CNVs (also picked by NETBAG)—CHD2, SYNGAP1, and SYNCRIP—are also affected by LoF de novo SNVs in ID,50,52 and two (SYNGAP1 and DPYD [MIM 612779]) are altered in schizophrenia.53”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [50] Rauch, 2012, Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study, Lancet source

      Not checked in the free run.

    • cites [52] de Ligt, 2012, Diagnostic exome sequencing in persons with severe intellectual disability, N. Engl. J. Med. source

      Not checked in the free run.

    • cites [53] Xu, 2012, De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia, Nat. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PI3K is regulated by FMRP, is elevated in FXS mouse knockouts, and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.

    “PI3K, which is regulated by FMRP,59 is elevated in FXS mouse knockouts,62,63 and downregulation of this pathway has been shown to have therapeutic effect in ASD and FXS mouse models.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [59] Ascano, 2012, FMRP targets distinct mRNA sequence elements to regulate protein expression, Nature source

      Not checked in the free run.

    • cites [62] Gross, 2010, Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome, J. Neurosci. source

      Not checked in the free run.

    • cites [63] Sharma, 2010, Dysregulation of mTOR signaling in fragile X syndrome, J. Neurosci. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    Control subjects were genotyped on the same array platforms as ASD subjects and parents and were analyzed with the same quality-control procedures and CNV analysis pipeline.

    “Samples were genotyped on the same array platforms (Illumina 1M single or duo arrays) as those of ASD subjects and parents and were analyzed with the same quality-control (QC) procedures and CNV analysis pipeline.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Rare de novo CNVs, clinically relevant CNVs, and other selected rare CNVs were validated by at least one method (quantitative PCR, MLPA, and/or long-range PCR).

    “Rare de novo CNVs, clinically relevant CNVs, and other selected rare CNVs were validated by at least one method (quantitative PCR, MLPA, and/or long-range PCR).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The majority of the 97 genes in the CNV or SNV network (not including genes already known to be involved in ASD) most likely act via haploinsufficiency, while a few are affected by duplications.

    “Whereas the majority of the 97 genes in the CNV or SNV network (not including the genes already known to be involved in ASD) most likely act via haploinsufficiency, a few are affected by duplications.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Affected AGP participants were classified according to the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview, Revised (ADI-R).

    “Affected AGP participants were classified according to the Autism Diagnostic Observation Schedule (ADOS)22 and the Autism Diagnostic Interview, Revised (ADI-R).23”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Lord, 1989, Autism diagnostic observation schedule: a standardized observation of communicative and social behavior, J. Autism Dev. Disord. source

      Not checked in the free run.

    • cites [23] Lord, 1994, Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders, J. Autism Dev. Disord. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Other chromatin regulator genes, such as MBD5 and KMT2D, have been implicated in ID and ASD.

    “Other chromatin regulator genes, such as MBD5 (MIM 611472) and KMT2D (MIM 602113), have been implicated in ID and ASD, highlighting the need to further study this category of genes as ASD risk factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The duplication of PIK3CB is likely to increase its expression and thus lead to excessive PI3K activity.

    “One example is the duplication of PIK3CB (MIM 602925), which is likely to increase its expression and thus lead to excessive phosphatidylinositol 3-kinase (PI3K) activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CHD2 and SYNGAP1 are both involved in autosomal-dominant ID, ASD, and epilepsy.

    “CHD2 (discussed above) and SYNGAP1 (encoding a Ras/Rap GTP-activating protein) are both involved in autosomal-dominant ID, ASD, and epilepsy.54”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Berryer, 2013, Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency, Hum. Mutat. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The clinical relevance of CNVs was interpreted according to the American College of Medical Genetics guidelines irrespective of the subjects' affected status.

    “The clinical relevance of CNVs was interpreted according to the American College of Medical Genetics guidelines32 irrespective of the subjects’ affected status, and CNVs were classified as pathogenic, uncertain, or benign.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Kearney, 2011, American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants, Genet. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Our data show that ASD-associated deletions impair synapse function and neurodevelopmental processes.

    “(8) show that ASD-associated deletions impair synapse function and neurodevelopmental processes;”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An increasing number of genes involved in chromatin structure and epigenetic regulation have been implicated in a variety of developmental disorders.

    “An increasing number of genes involved in chromatin structure and epigenetic regulation have been implicated in a variety of developmental disorders.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Day, 2011, Epigenetic mechanisms in cognition, Neuron source

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    Unrelated control subjects from SAGE, the Ontario Colorectal Cancer Case-Control Study, and HABC, who had no obvious psychiatric history, are valid controls for ASD CNV burden analyses.

    “Unrelated control subjects were assembled from three studies in which individuals had no obvious psychiatric history: the Study of Addiction Genetics and Environment (SAGE),26 the Ontario Colorectal Cancer Case-Control Study,27,28 and Health, Aging, and Body Composition (HABC) (Table S1B).29”

  • The paper relies on this without support.

    The published control de novo CNV datasets (unaffected siblings from the Simons Simplex Collection and Icelandic control trios) are comparable to the AGP affected subjects for CNV size and gene-content comparisons.

    “Secondary analyses included comparisons of CNV number, length, and intersected gene number between our 102 de novo CNVs identified in affected subjects and the 76 de novo CNVs in control subjects of two published data sets: (1) 17 de novo CNVs identified in 15 unaffected siblings from 872 families with a single ASD-affected offspring and an unaffected sibling from the Simons Simplex Collection4”

  • The authors state this as an assumption.

    If genomic regions are perturbed by genetic variants associated with the same phenotype, they will contain genes forming connected clusters.

    “NETBAG identifies networks of genes under the premise that if genomic regions are perturbed by genetic variants associated with the same phenotype, they will contain genes forming connected clusters.”

  • The authors state this as an assumption.

    Different genes harboring suspected causative mutations for the same disorder often physically interact.

    “Under the assumption that different genes harboring suspected causative mutations for the same disorder often physically interact, we sought to evaluate protein-protein interactions (PPIs) encoded by genes known to be implicated in ASD and genes affected by rare CNVs or SNVs”
4 of 4

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?

  • Genes within ASD CNVs are highly connected with each other and with other ASD genes.

    “Studies of large CNVs in ASD have shown that genes within ASD CNVs are highly connected with each other (Corominas et al., 2014) and with other ASD genes (Pinto et al., 2014).”

    From Getting to the cores of autism (2019) · cites this paper as Pinto et al., 2014

  • The ASD [Pinto] list comprises 124 genes implicated in ASD and ID, updated from a list by Betancur in 2011.

    “(iv) Pinto et al.33 compiled a list of 124 genes (ASD [Pinto]) that have been implicated in ASD and was updated from a list provided by Betancur in 2011 (ref. 55). All of the 124 genes have also been implicated in ID.”

    From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [33]

  • Subsets of human genes have been previously identified as missense constrained or loss-of-function intolerant.

    “Subsets of human genes have been previously identified as “missense constrained” (based on a lack of functional coding variation in controls) or “loss-of-function intolerant” (based on a smaller-than-expected number of loss-of-function mutations in population-scale data)13,21.”

    From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [21]

  • Studies on hcASD genes and iPSC-derived ASD neurons highlight signaling pathways that are commonly disrupted, such as PI3K/AKT, RAS/ERK, WNT and β-catenin.

    “Consistently, studies on hcASD genes and iPSC-derived ASD neurons highlight signaling pathways that are commonly disrupted, such as PI3K/AKT [79, 80], RAS/ERK [79, 80, 82, 83], WNT and β-catenin [57, 83, 84].”

    From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [79]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Control-group totals do not add up

    Minor

    The 2,640 European controls plus 1,843 controls of other ancestries total 4,483, not 4,768.

    Reported 4768 · recomputed 4483

1 of 1

Cites

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1 of the 66 references couldn’t be matched to a known paper.

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Related

Authors
Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., Vorstman, J. A. S., Thompson, A., Regan, R., Pilorge, M., Pellecchia, G., Pagnamenta, A. T., Oliveira, B., Marshall, C. R., Magalhaes, T. R., Lowe, J. K., Howe, J. L., Griswold, A. J., Gilbert, J., Duketis, E., Dombroski, B. A., De Jonge, M. V., Cuccaro, M., Crawford, E. L., Correia, C. T., Conroy, J., Conceição, I. C., Chiocchetti, A. G., Casey, J. P., Cai, G., Cabrol, C., Bolshakova, N., Bacchelli, E., Anney, R., Gallinger, S., Cotterchio, M., Casey, G., Zwaigenbaum, L., Wittemeyer, K., Wing, K., Wallace, S., van Engeland, H., Tryfon, A., Thomson, S., Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McInnes, L. A., McGrew, S. G., Lord, C., Leboyer, M., Le Couteur, A. S., Kolevzon, A., Jiménez González, P., Jacob, S., Holt, R., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B. A., Duque, F., Delorme, R., Dawson, G., Chaste, P., Café, C., Brennan, S., Bourgeron, T., Bolton, P. F., Bölte, S., Bernier, R., Baird, G., Bailey, A. J., Anagnostou, E., Almeida, J., Wijsman, E. M., Vieland, V. J., Vicente, A. M., Schellenberg, G. D., Pericak-Vance, M., Paterson, A. D., Parr, J. R., Oliveira, G., Nurnberger, J. I., Monaco, A. P., Maestrini, E., Klauck, S. M., Hakonarson, H., Haines, J. L., Geschwind, D. H., Freitag, C. M., Folstein, S. E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J. S., Hallmayer, J., Gill, M., Cook, E. H., Buxbaum, J. D., Devlin, B., Gallagher, L., Betancur, C., & Scherer, S. W.
Affiliations
  • Icahn School of Medicine at Mount Sinai (US)
  • Centre National de la Recherche Scientifique (FR)
  • Hospital for Sick Children (CA)
  • Trinity College Dublin (IE)
  • University of Pittsburgh (US)
  • University Medical Center Utrecht (NL)
  • McMaster University (CA)
  • University College Dublin (IE)
  • Centre for Human Genetics (GB)
  • University of Lisbon (PT)
  • University of Toronto (CA)
  • University of California, Los Angeles (US)
  • University of Miami (US)
  • Goethe University Frankfurt (DE)
  • University of Pennsylvania (US)
  • Vanderbilt University (US)
  • University of Bologna (IT)
  • Cancer Care Ontario (CA)
  • University of Southern California (US)
  • University of Alberta (CA)
  • University of Birmingham (GB)
  • Warneford Hospital (GB)
  • Laboratoire de NeuroPsychoLinguistique (FR)
  • Unidade Local de Saúde de Coimbra (PT)
  • Weill Cornell Medical Center (US)
  • Inserm (FR)
  • University of Minnesota (US)
  • University of Illinois Chicago (US)
  • Manchester Academic Health Science Centre (GB)
  • University of Gothenburg (SE)
  • Memorial University of Newfoundland (CA)
  • King's College London (GB)
  • University of Washington (US)
  • Nationwide Children's Hospital (US)
  • Newcastle University (GB)
  • Tufts University (US)
  • German Cancer Research Center (DE)
  • Children's Hospital of Philadelphia (US)
  • University of Utah (US)
  • Stanford Medicine (US)
Corresponding author
  • Betancur, Catalina
  • Scherer, Stephen W.
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2014-05
Volume
94
Issue
5
Pages
677-694
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2014.03.018
PMC
PMC4067558
OpenAlex
W2129867386
Semantic Scholar
243b54688dac51ccb4b409e63029323c9858f738
Cited by
969
References
66
Citations by year
2026: 26 · 2025: 35 · 2024: 62 · 2023: 63 · 2022: 80 · 2021: 98 · 2020: 100 · 2019: 91 · 2018: 80 · 2017: 100 · 2016: 102 · 2015: 92 · 2014: 40
FWCI
62.30
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by-nc-nd)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • PMC
  • Newcastle University ePrints (Newcastle Univesity) (cc-by-nc-nd)
Funders
  • Brain and Behavior Research Foundation
  • Medical Research Council
  • Genome Canada
  • Hospital for Sick Children
  • National Alliance for Research on Schizophrenia and Depression
  • Health Research Board (AUT/2006/1, AUT/2006/2, PD/2006/48)
  • Ontario Genomics Institute
  • Canadian Institutes of Health Research
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 › Genomic variations and chromosomal abnormalities
Keywords
autism spectrum disorder, copy number variation, de novo CNVs, intellectual disability, CHD2, HDAC4, GDI1, SETD5, microRNA-137, HDAC9, neuronal signaling, synaptic function, chromatin regulation, gene networks
MeSH terms
Child, Child Development Disorders, Pervasive, Female, Multigene Family, Humans, Male, Pedigree, Sequence Deletion, Gene Regulatory Networks, Metabolic Networks and Pathways, DNA Copy Number Variations

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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