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Cited by 423Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomic variations and chromosomal abnormalities

A de novo convergence of autism genetics and molecular neuroscience

Open access
Krumm, Niklas, O’Roak, Brian J., Shendure, Jay, Eichler, Evan E.·2014·Trends in Neurosciences
DOI 10.1016/j.tins.2013.11.005PMC PMC4077788
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Abstract

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with large genetic components, but identification of pathogenic genes has proceeded slowly because hundreds of loci are involved. 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. Targeted large-scale resequencing studies have confirmed the significance of specific loci, including chromodomain helicase DNA binding protein 8 (CHD8), sodium channel, voltage-gated, type II, alpha subunit (SCN2A), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), and catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1, beta-catenin). We review recent studies and suggest that they have led to a convergence on three functional pathways: (i) chromatin remodeling; (ii) wnt signaling during development; and (iii) synaptic function. These pathways and genes significantly expand the neurobiological targets for study, and suggest a path for future genetic and functional studies.

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Crossref · 10.1016/j.tins.2013.11.005

Cites

Statistics

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Claims the paper makes

0 of 89 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    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].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Iossifov I De novo gene disruptions in children on the autistic spectrum Neuron 2012 74 285 299 22542183 PMC3619976 source

      Not checked in the free run.

    • cites [27] Sanders SJ De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature 2012 485 237 241 22495306 PMC3667984 source

      Not checked in the free run.

  • Findingcitation

    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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Iossifov I De novo gene disruptions in children on the autistic spectrum Neuron 2012 74 285 299 22542183 PMC3619976 source

      Not checked in the free run.

    • cites [27] Sanders SJ De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature 2012 485 237 241 22495306 PMC3667984 source

      Not checked in the free run.

  • Findingown data

    Genes with mutations in siblings or synonymous mutations in probands or siblings show no difference from the null network distribution.

    “by contrast, neither the genes with mutations in siblings, nor those with synonymous mutations (in either proband or siblings) showed any difference from the null distribution of networks (Table S1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein-protein interaction network connectivity indicates shared biological pathways relevant to ASD/ID.
  • Findingcitation

    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.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [24] O’Roak BJ Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature 2012 485 246 250 22495309 PMC3350576 source

      Not checked in the free run.

    • cites [25] Neale BM Patterns and rates of exonic de novo mutations in autism spectrum disorders Nature 2012 485 242 245 22495311 PMC3613847 source

      Not checked in the free run.

    • cites [26] Iossifov I De novo gene disruptions in children on the autistic spectrum Neuron 2012 74 285 299 22542183 PMC3619976 source

      Not checked in the free run.

    • cites [27] Sanders SJ De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature 2012 485 237 241 22495306 PMC3667984 source

      Not checked in the free run.

    • cites [28] de Ligt J Diagnostic exome sequencing in persons with severe intellectual disability N. Engl. J. Med 2012 367 1921 1929 23033978 source

      Not checked in the free run.

    • cites [29] Rauch A Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Lancet 2012 380 1674 1682 23020937 source

      Not checked in the free run.

  • Findingown data

    For CHD8, GRIN2B, and DYRK1A, no truncating variants were observed in the NHLBI Exome Sequencing Project.

    “For several of these genes with recurrent de novo hits in ASD probands (CHD8, GRIN2B, DYRK1A), no truncating variants were observed in the ESP.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The NHLBI Exome Sequencing Project samples are an appropriate control set for comparing mutation frequencies.
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingcitation

    DYRK1A has three truncating mutations in autism probands and de novo structural variants in ID probands.

    “Another striking candidate is DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A), for which three truncating mutations have been discovered in autism probands [24,44] and de novo structural variants in ID probands [54,55].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [24] O’Roak BJ Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature 2012 485 246 250 22495309 PMC3350576 source

      Not checked in the free run.

    • cites [44] O’Roak BJ Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders Science 2012 338 1619 1622 23160955 PMC3528801 source

      Not checked in the free run.

    • cites [54] van Bon BWM Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly Clin. Genet 2011 79 296 299 21294719 source

      Not checked in the free run.

    • cites [55] Moller RS Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly Am. J. Hum. Genet 2008 82 1165 1170 18405873 PMC2427221 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    A set of 11 genes shows enrichment in ASD/ID cases and accounts for approximately 2.2% of all cases.

    “In summary, when considering only protein-disruptive mutations from six exome sequencing studies (four ASD and two ID) and including the resequencing of some of these candidate genes, a set of 11 genes (Table 2) show enrichment in cases with ASD/ID and account for approximately 2.2% of all cases.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The six exome studies and resequencing cohorts can be combined to estimate gene-level enrichment and the overall fraction of ASD/ID cases explained.

  • May combine two claims.

    Findingown data

    The PPI network based on all truncating and missense mutations in probands is significantly more clustered, has more edges, and has larger connected components than random or permuted networks, with P ≤ 0.009 for all tests.

    “We found that the PPI network based on all truncating and missense mutations in probands was significantly more clustered, had more edges, and created larger connected components than randomly sampled or permuted networks (P ≤ 0.009 for all tests; see the supplementary material online)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein-protein interaction network connectivity indicates shared biological pathways relevant to ASD/ID.

  • May combine two claims.

    Findingown data

    MIP resequencing of 44 candidate genes in 2446 ASD probands yielded 27 new de novo mutations across 16 genes, of which 17 were disruptive SNVs, a fraction higher than expected by chance.

    “Altogether, this assay yielded 27 new de novo mutations across 16 genes; of these mutations, 17 were disruptive SNVs, a fraction higher than expected by chance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] O’Roak BJ Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders Science 2012 338 1619 1622 23160955 PMC3528801 source

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    All three human loss-of-function DYRK1A autism patients are cognitively impaired and microcephalic with Z-score below −2.

    “Consistent with these models, all three human loss-of-function autism patients are cognitively impaired and microcephalic (Z-score < −2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    CHD8 mutation frequency is the highest of all genes screened and nearly matches the frequency of CNVs at 16p11.2, the most frequent recurrent deletion or duplication locus in sporadic ASD.

    “The frequency of mutations in this gene is the highest of all genes screened thus far and nearly matches that of CNVs at 16p11.2, which is the most frequent recurrently deleted (0.5%) or duplicated (0.3%) locus in sporadic ASD [50,51].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Kumar RA Association and mutation analyses of 16p11.2 autism candidate genes PLoS ONE 2009 4 http://dx.doi.org/10.1371/journal.pone.0004582 PMC2644762 19242545 source

      Not checked in the free run.

    • cites [51] Walsh KM Bracken MB Copy number variation in the dosage-sensitive 16p11.2 interval accounts for only a small proportion of autism incidence: a systematic review and meta-analysis Genet. Med 2011 13 377 384 21289514 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    About 8% of sporadic ASD cases carry a de novo CNV, compared with 2% of unaffected siblings.

    “Both initial and subsequent higher-resolution studies estimate that 8% of sporadic ASD cases carried a de novo CNV, as compared with only 2% of unaffected siblings [11,12].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Levy D Rare de novo and transmitted copy-number variation in autistic spectrum disorders Neuron 2011 70 886 897 21658582 source

      Not checked in the free run.

    • cites [12] Sanders SJ Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism Neuron 2011 70 863 885 21658581 PMC3939065 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A follow-up case-control study of 935 cases found three additional truncating CHD8 mutations and one splice-site SCN2A mutation, strengthening the initial associations.

    “Notably, however, a follow-up case-control study by Neale and colleagues of 935 cases found three additional truncating CHD8 mutations and one splice-site mutation in SCN2A, further strengthening the initial disease associations of these genes [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Neale BM Patterns and rates of exonic de novo mutations in autism spectrum disorders Nature 2012 485 242 245 22495311 PMC3613847 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The two largest connected components of the combined network encompass postsynaptic scaffolding proteins and receptors, and WNT signaling and chromatin remodeling functions anchored by CHD8.

    “The two largest connected components of this combined network encompass three broad functional pathways: the first connected component (13 proteins) forms a highly interconnected set of postsynaptic scaffolding proteins and receptors, including SYNGAP1, discs large homolog 4 (DLG4, Drosophila), GRIN2A/B, NLGN1, and NRXN1, whereas the second (nine proteins) contains both WNT signaling functions of”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein-protein interaction network connectivity indicates shared biological pathways relevant to ASD/ID.

  • May combine two claims.

    Findingcitation

    SCN2A is the second strongest overall association, with two truncating mutations in ASD cases and three in ID cases.

    “The second strongest overall association, with two truncating mutations in ASD cases and three such mutations in ID cases, is SCN2A, a gene previously associated with epilepsy and seizure disorders [52,53].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Kamiya K A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline J. Neurosci 2004 24 2690 2698 15028761 PMC6729532 source

      Not checked in the free run.

    • cites [53] Ogiwara I De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies Neurology 2009 73 1046 1053 19786696 PMC2754324 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    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.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [24] O’Roak BJ Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature 2012 485 246 250 22495309 PMC3350576 source

      Not checked in the free run.

    • cites [25] Neale BM Patterns and rates of exonic de novo mutations in autism spectrum disorders Nature 2012 485 242 245 22495311 PMC3613847 source

      Not checked in the free run.

    • cites [26] Iossifov I De novo gene disruptions in children on the autistic spectrum Neuron 2012 74 285 299 22542183 PMC3619976 source

      Not checked in the free run.

    • cites [27] Sanders SJ De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature 2012 485 237 241 22495306 PMC3667984 source

      Not checked in the free run.

    • cites [28] de Ligt J Diagnostic exome sequencing in persons with severe intellectual disability N. Engl. J. Med 2012 367 1921 1929 23033978 source

      Not checked in the free run.

    • cites [29] Rauch A Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Lancet 2012 380 1674 1682 23020937 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    MIP resequencing confirmed ASD association for CHD8 and DYRK1A and provided statistical support for GRIN2B, TBR1, PTEN, and TBL1XR1.

    “The discovery of these mutations confirmed the association with ASD for CHD8 and DYRK1A and provided significant statistical support for four novel genes: GRIN2B (glutamate receptor, ionotropic, N-methyl d-aspartate 2B), TBR1 (T-box brain gene 1), PTEN (phosphatase and tensin homolog), and TBL1XR1 [transducin (beta)-like 1 X-linked receptor 1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] O’Roak BJ Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders Science 2012 338 1619 1622 23160955 PMC3528801 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Among 593 ASD quads, there were 80 disruptive de novo mutations in probands and 36 in siblings, with an odds ratio of 2.41 and P < 1 × 10−4.

    “Overall, among the 593 ASD quads, there were 80 such mutations in probands with ASD, but only 36 in siblings [odds ratio (OR) = 2.41, P < 1 × 10−4, Fisher’s exact test; Table 1].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Missense mutation enrichment in probands is weak, with an odds ratio of 1.29 and P = 0.03 across all quads.

    “The reported enrichment of missense mutations in probands has been less robust, with study estimates for enrichment between 1- and 1.34-fold, but analysis of all quads does show weak statistical enrichment (OR = 1.29, P = 0.03).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Control mutations in SYNGAP1 occur at 3.2% frequency but are located near the carboxy terminus outside functional domains and are unlikely to affect protein function.

    “while control mutations are sometimes found in genes in high frequency (e.g., frameshift in SYNGAP1 at 3.2% frequency in controls), these mutations are found exclusively near the carboxy terminus of the protein and outside of functional protein domains and are unlikely to affect protein function (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CHD8 has the strongest overall association, with eight de novo truncating mutations observed across 2597 cases and none in control siblings or over 6500 ESP exomes.

    “Overall, eight de novo truncating mutations were observed across 2597 cases in this gene; by contrast, no such mutations were observed in control siblings, or in over 6500 exomes in the ESP.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] O’Roak BJ Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders Science 2012 338 1619 1622 23160955 PMC3528801 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    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.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [24] O’Roak BJ Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature 2012 485 246 250 22495309 PMC3350576 source

      Not checked in the free run.

    • cites [25] Neale BM Patterns and rates of exonic de novo mutations in autism spectrum disorders Nature 2012 485 242 245 22495311 PMC3613847 source

      Not checked in the free run.

    • cites [26] Iossifov I De novo gene disruptions in children on the autistic spectrum Neuron 2012 74 285 299 22542183 PMC3619976 source

      Not checked in the free run.

    • cites [27] Sanders SJ De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature 2012 485 237 241 22495306 PMC3667984 source

      Not checked in the free run.

    • cites [28] de Ligt J Diagnostic exome sequencing in persons with severe intellectual disability N. Engl. J. Med 2012 367 1921 1929 23033978 source

      Not checked in the free run.

    • cites [29] Rauch A Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Lancet 2012 380 1674 1682 23020937 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In follow-up MIP resequencing, 94% of newly discovered truncating mutations fell within the network or an expanded network, an observation unlikely by chance with P = 0.0002.

    “Notably, in follow-up MIP resequencing, we targeted ~50% network and ~50% non-network genes and found that 94% (16/17) of the newly discovered truncating mutations fell within the network (or a similar, expanded 74-gene network) – an observation unlikely to have occurred by chance (P = 0.0002).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Protein-protein interaction network connectivity indicates shared biological pathways relevant to ASD/ID.

  • May combine two claims.

    Findingcitation

    ASD cases with truncating CHD8 mutations have significant macrocephaly, whereas all three cases with truncating beta-catenin mutations have microcephaly.

    “Strikingly, ASD cases with truncating mutations in CHD8 have significant macrocephaly [44], whereas all three cases with truncating mutations in beta-catenin have microcephaly ([28]; B.J. O’Roak, unpublished).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] O’Roak BJ Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders Science 2012 338 1619 1622 23160955 PMC3528801 source

      Not checked in the free run.

    • cites [28] de Ligt J Diagnostic exome sequencing in persons with severe intellectual disability N. Engl. J. Med 2012 367 1921 1929 23033978 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    De novo CNVs are likely highly deleterious and highly penetrant mutations.

    “The de novo nature of these CNVs, together with their absence in the general population, suggests they represent a class of highly deleterious and highly penetrant mutations.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Rare large de novo CNVs are thought to account for up to 15% of disease burden among children with developmental delay and intellectual disability.

    “Furthermore, among children with general developmental delay (DD) and ID, rare large de novo CNVs are thought to account for up to 15% of disease burden [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Cooper GM A copy number variation morbidity map of developmental delay Nat. Genet 2011 43 838 846 21841781 PMC3171215 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Recurrent CNVs initially observed in ID or ASD are also found in adults with epilepsy, bipolar disorder, or schizophrenia, suggesting genetic overlap among these disorders.

    “many of these same recurrent CNVs observed initially in patients with ID [15] or ASD [16] have been identified in adults with epilepsy [17], bipolar disorder [18], or schizophrenia [19,20], suggesting overlap in the genetic etiology of these disorders.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Helbig I 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy Nat. Genet 2009 41 160 162 19136953 PMC3026630 source

      Not checked in the free run.

    • cites [18] Ben-Shachar S Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders J. Med. Genet 2009 46 382 388 19289393 PMC2776649 source

      Not checked in the free run.

    • cites [19] Stefansson H Large recurrent microdeletions associated with schizophrenia Nature 2008 455 232 236 18668039 PMC2687075 source

      Not checked in the free run.

    • cites [20] International Schizophrenia Consortium Rare chromosomal deletions and duplications increase risk of schizophrenia Nature 2008 455 237 241 18668038 PMC3912847 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    SCN2A mutations have highly variable phenotypic outcomes, as only one of five cases had a history of seizures.

    “Lastly, only one of the five cases had a history of seizures [28], suggesting that mutations in SCN2A have highly variable phenotypic outcomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] de Ligt J Diagnostic exome sequencing in persons with severe intellectual disability N. Engl. J. Med 2012 367 1921 1929 23033978 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    No single gene will account for more than 1% of autism cases; rather, rare mutations in hundreds of genes may contribute to ASD or ID.

    “Both CNV and exome sequencing data suggest that no single gene will account for more than 1% of autism cases; rather, rare mutations in hundreds of genes may contribute to ASD or ID.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Although individual CNVs are rare, together they account for a significant fraction of ASD/ID cases, indicating considerable locus heterogeneity.

    “Although specific CNVs are individually rare, combined they account for a significant fraction of cases, indicating the presence of considerable locus heterogeneity of ASD and ID.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Recent studies converge on three functional pathways: chromatin remodeling, Wnt signaling during development, and synaptic function.

    “We review recent studies and suggest that they have led to a convergence on three functional pathways: (i) chromatin remodeling; (ii) wnt signaling during development; and (iii) synaptic function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Quad-based designs are more informative for observed mutation rates than trio-based or case-control designs, which are susceptible to stratification effects.

    “By contrast, trio-based and case-control study designs are less informative with respect to observed mutation rates and are susceptible to stratification effects [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Gratten J Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease Nat. Genet 2013 45 234 238 23438595 source

      Not checked in the free run.

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

    Study design and conductown data

    Our network does not distinguish interaction types (regulatory or physical) or cellular compartments.

    “in our network we do not distinguish between different interaction types (regulatory or physical) or cellular compartments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    There is compelling evidence that DYRK1A and CHD8 mutations define microcephalic and macrocephalic subtypes, respectively.

    “There is already compelling evidence for this based on an assessment of multiple patients with DYRK1A and CHD8 mutations, which appear to define microcephalic and macrocephalic subtypes, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    This model resembles heterogeneity in other broad human disorders and has succeeded in many cases.

    “This model is akin to the heterogeneity seen in other broad categories of human disorders and disease and has proven to be successful in many cases”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The NETBAG model using CNV data from SSC families showed enrichment of the canonical WNT pathway, postsynaptic complexes, dendritic spine development, and chromatin remodeling proteins.

    “In particular, their model showed enrichment of the canonical WNT pathway, postsynaptic complexes, and dendritic spine development (e.g., DLG4, SYNGAP1) and several proteins involved in chromatin remodeling, including bromodomain adjacent to zinc finger domain 1B (BAZ1B) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 (SMARCA2), both of which”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Gilman SR Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses Neuron 2011 70 898 907 21658583 PMC3607702 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Better knowledge of ASD genetic and neurobiological causes will help diagnose ASD/ID subtypes, enabling targeted trial recruitment and therapeutics.

    “Improving knowledge of ASD genetic and neurobiological etiologies will aid in diagnosis of ASD/ID subtypes, allowing for specific recruitment for clinical trials and the development of targeted therapeutics for each subtype.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Interaction impact and weight vary greatly across nodes, especially hub nodes that can interact with hundreds of proteins.

    “the impact and weight of interactions can vary considerably for different nodes, especially for ‘hub’ nodes, which can interact with hundreds of other proteins.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CHD7 is responsible for CHARGE syndrome.

    “CHD7 [47], which is responsible for CHARGE syndrome”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Batsukh T CHD8 interacts with CHD7, a protein which is mutated in CHARGE syndrome Hum. Mol. Genet 2010 19 2858 2866 20453063 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    Protein interactions are hard to assay experimentally and often not at proteomic scale, causing false negatives and false positives in databases.

    “protein interactions are difficult to assay experimentally and often are not at a proteomic scale, resulting in false negatives and false positives in databases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Coffin-Siris syndrome is characterized by ID and severe speech delays and is caused by truncating mutations or disruptive CNVs in ARID1B.

    “Coffin-Siris syndrome (OMIM 135900), characterized by ID and severe speech delays, was recently attributed to truncating mutations or disruptive CNVs in ARID1B”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Santen GWE Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome Nat. Genet 2012 44 379 380 22426309 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    De novo mutations point to genes involved in synaptic function and localization, a pathway already suspected to be disrupted in ASD.

    “de novo mutations also highlight the importance of genes with roles in synaptic function and localization – a pathway previously suspected to be disrupted in ASD [78].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Glessner JT Autism genome-wide copy number variation reveals ubiquitin and neuronal genes Nature 2009 459 569 573 19404257 PMC2925224 source

      Not checked in the free run.

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

    Premisecitation

    CASK binds NRXN1 presynaptically, but its binding to TBR1 occurs in the nucleus.

    “whereas CASK binds NRXN1 presynaptically [82], binding to the transcription factor TBR1 is in the nucleus [83].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Fairless R Polarized targeting of neurexins to synapses is regulated by their C-terminal sequences J. Neurosci 2008 28 12969 12981 19036990 PMC6671796 source

      Not checked in the free run.

    • cites [83] Hsueh Y-P Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2 Nature 2000 404 298 302 10749215 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Beta-catenin, through downstream WNT pathways, influences neuronal migration, polarity, and synaptogenesis, and its constitutive overexpression in mice causes macrocephaly.

    “Beta-catenin, via downstream WNT pathways, influences neuronal migration, polarity, and synaptogenesis [71], and constitutive overexpression of beta-catenin in mice results in macrocephaly [72].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Salinas PC Zou Y Wnt signaling in neural circuit assembly Annu. Rev. Neurosci 2008 31 339 358 18558859 source

      Not checked in the free run.

    • cites [72] Chenn A Walsh CA Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice Cereb. Cortex 2003 13 599 606 12764034 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in KANSL1 cause 17q21.31 microdeletion syndrome, a condition with ID as a characteristic feature.

    “were recently found to underlie 17q21.31 microdeletion syndrome, in which ID is a characteristic feature [77]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Koolen DA Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome Nat. Genet 2012 44 639 641 22544363 source

      Not checked in the free run.

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

    Interpretationreasoning

    The lack of KANSL1 mutations in ASD cases is probably because known clinical syndromes were excluded from those cohorts.

    “although this is likely to be due to exclusion of known clinical syndromes from these cohorts.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Our PPI network uses only experimentally verified interactions.

    “although our PPI network only uses experimentally verified interactions”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The available exomes are significantly imbalanced between ASD (n = 593) and ID (n = 151), so comparisons need caution.

    “although the significant imbalance in the number of available exomes for ASD (n = 593) and ID (n = 151) advises caution in these comparisons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CHD8 has ATP-dependent chromatin remodeling activity and directly interacts with CHD7.

    “CHD8 possesses ATP-dependent chromatin remodeling activity and directly interacts with CHD7 [47]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Batsukh T CHD8 interacts with CHD7, a protein which is mutated in CHARGE syndrome Hum. Mol. Genet 2010 19 2858 2866 20453063 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SHANK3 is a known ASD protein with mutation frequency up to 1% in ASD cases.

    “a previously identified ASD protein with up to 1% mutation frequency in ASD cases [80,81]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [80] Durand CM Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders Nat. Genet 2007 39 25 27 17173049 PMC2082049 source

      Not checked in the free run.

    • cites [81] Moessner R Contribution of SHANK3 mutations to autism spectrum disorder Am. J. Hum. Genet 2007 81 1289 1297 17999366 PMC2276348 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CHD8 negatively regulates beta-catenin through direct binding and downregulates beta-catenin-responsive genes by recruiting to their promoters.

    “CHD8 negatively regulates beta-catenin via direct binding and, furthermore, downregulates beta-catenin-responsive genes by recruitment to their promoter regions [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Thompson BA CHD8 is an ATP-dependent chromatin remodeling factor that regulates beta-catenin target genes Mol. Cell. Biol 2008 28 3894 3904 18378692 PMC2423111 source

      Not checked in the free run.

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

    Premisecitation

    NRXN1 has previously been linked to ASD.

    “NRXN1, which has been previously associated with ASD [42]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Kim H-G Disruption of neurexin 1 associated with autism spectrum disorder Am. J. Hum. Genet 2008 82 199 207 18179900 PMC2253961 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fragile-X pathway-correcting therapies have shown promise in mice and are in Phase II trials.

    “the emergence of therapies designed to correct specific pathways disrupted in Fragile-X; these have shown promise in mouse models [89] and are currently undergoing Phase II clinical trials.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Michalon A Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice Neuron 2012 74 49 56 22500629 PMC8822597 source

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    The six exome studies and resequencing cohorts can be combined to estimate gene-level enrichment and the overall fraction of ASD/ID cases explained.

    “In summary, when considering only protein-disruptive mutations from six exome sequencing studies (four ASD and two ID) and including the resequencing of some of these candidate genes, a set of 11 genes (Table 2) show enrichment in cases with ASD/ID and account for approximately 2.2% of all cases.”

  • The paper relies on this without support.

    The NHLBI Exome Sequencing Project samples are an appropriate control set for comparing mutation frequencies.

    “we have summarized the distribution of mutations, as well as the prevalence and coding location of mutations found in exome sequence from 6503 samples from the NHLBI Exome Sequencing Project (ESP) in Table 2.”

  • The paper relies on this without support.

    Protein-protein interaction network connectivity indicates shared biological pathways relevant to ASD/ID.

    “These networks provide a powerful method to unify the landscape of mutations observed in genetically heterogeneous human disorders by leveraging regulatory interactions between genes and/or physical interactions between proteins.”

  • The paper relies on this without support.

    PPI network connectivity reflects biologically relevant functional relationships for ASD and ID.

    “Interaction networks (Figure 3) can also suggest novel targets for mutation screens or functional studies.”

  • The paper relies on this without support.

    The six ASD/ID exome studies are sufficiently comparable to combine for network analysis and mutation frequency comparisons.

    “In examining data presented in this review, several observations regarding the genetic or etiologic differences between ASD and ID diagnoses emerge, although the significant imbalance in the number of available exomes for ASD (n = 593) and ID (n = 151) advises caution in these comparisons.”
5 of 5

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?

  • Genetic studies have identified about 20-30% of the sought-after ASD genes.

    “Thus, it seems remarkable that within just the last few years, genetic studies have identified a sizeable fraction of the sought-after ASD genes, roughly 20-30% according to most estimates (Bourgeron, 2015; Krumm et al., 2014; Schaaf and Zoghbi, 2011).”

    From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Krumm et al., 2014

  • CHD8 is an ASD gene highlighted by multiple genetic studies.

    “One supporting argument derives from the clear role of CHD8 (not to be confused with CDH8), an ASD gene highlighted by multiple genetic studies (Krumm et al., 2014).”

    From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Krumm et al., 2014

  • Putative loss-of-function mutations in CHD8 and CTNNB1 have opposite effects on brain growth in ASD probands.

    “This may explain why putative loss of function mutations of CHD8 and CTNNB1 exert opposite effects on brain growth in ASD probands (Chenn and Walsh, 2002; Krumm et al., 2014).”

    From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Krumm et al., 2014

  • Studies on CHD8 and iPS-derived ASD neurons indicate the dysregulation of proliferation and macrocephaly in ASD could be linked to the disruption of these signaling pathways and shortened G1/S transition.

    “Studies on CHD8 and iPS-derived ASD neurons indicate the dysregulation of proliferation and macrocephaly in ASD could be linked to the disruption of these signaling pathways and shortened G1/S transition[54, 55, 57, 94, 183, 192, 193].”

    From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [57]

  • 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 [57]

The citation lists haven’t been fetched yet

References 90 · Cited by 423

Authors
Krumm, N., O’Roak, B. J., Shendure, J., & Eichler, E. E.
Affiliations
  • University of Washington (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Eichler, Evan E.
ORCID
Venue
Trends in Neurosciences
Publisher
Elsevier BV
Published
2014-02
Volume
37
Issue
2
Pages
95-105
ISSN
0166-2236 (ISSN-L)
DOI
10.1016/j.tins.2013.11.005
PMC
PMC4077788
OpenAlex
W2064332273
Semantic Scholar
4bad40e3b276f0645f00d7db3bab84a7daad275d
Cited by
423
References
90
Citations by year
2026: 9 · 2025: 12 · 2024: 18 · 2023: 21 · 2022: 20 · 2021: 27 · 2020: 36 · 2019: 29 · 2018: 49 · 2017: 49 · 2016: 60 · 2015: 62 · 2014: 31
FWCI
8.92
Type
journal article
Language
en
Open access
Locations
  • Trends in Neurosciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute of General Medical Sciences (T32GM007266)
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 › Genomic variations and chromosomal abnormalities
Keywords
autism spectrum disorder, intellectual disability, de novo mutations, rare variants, CHD8, SCN2A, DYRK1A, CTNNB1, chromatin remodeling, Wnt signaling, synaptic function, neurodevelopmental disorders, exome sequencing, resequencing
MeSH terms
Autistic Disorder, Humans, Neurosciences, Genetic Predisposition to Disease, Exome

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