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Cited by 1,263Genomic variations and chromosomal abnormalitiesWilliams Syndrome ResearchAutism Spectrum Disorder Research

Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism

Open access
Sanders, Stephan J., Ercan-Sencicek, A. Gulhan, Hus, Vanessa, Luo, Rui, Murtha, Michael T., Moreno-De-Luca, Daniel, Chu, Su H., Moreau, Michael P. +59 more·2011·Neuron
DOI 10.1016/j.neuron.2011.05.002PMC PMC3939065
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Abstract

We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 × 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2011.05.002

Cites

75 of 75 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 47 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Recurrent de novo duplications at 7q11.23 are significantly associated with ASD (4 duplications, p=7e-6).

    “the observation of 4 recurrent de novo duplications at 7q11.23 (p= 7 × 10−6)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The reciprocal deletion at 7q11.23 causes Williams-Beuren syndrome, which features a highly social personality.
  • Findingown data

    16p11.2 deletions are strongly associated with ASD when considered independently (N=7, p=2e-14).

    “16p11.2 deletions (N=7; p=2 × 10−14) and duplications (N=4; p=7 × 10−6) are strongly associated with ASD when considered independently”
    Quote in the paperSubstantial claim
  • Findingown data

    There are an estimated 130-234 distinct ASD-related CNV intervals across the genome.

    “estimate the presence of 130-234 distinct ASD-related CNV intervals across the genome”
    Quote in the paperNot a substantial claim
  • Findingown data

    Large de novo CNVs carry substantial risk for ASD (OR=3.55, CI=2.16-7.46, p=6.9e-6).

    “Overall, we find large de novo CNVs carry substantial risk (OR=3.55; CI =2.16-7.46, p=6.9 × 10−6)”
    Quote in the paperSubstantial claim
  • Findingown data

    16p11.2 duplications are strongly associated with ASD when considered independently (N=4, p=7e-6).

    “16p11.2 deletions (N=7; p=2 × 10−14) and duplications (N=4; p=7 × 10−6) are strongly associated with ASD when considered independently”
    Quote in the paperSubstantial claim
  • May combine two claims. 36
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    Rare de novo genic CNVs are more common in probands than siblings, with an OR of 4.02 (50 probands vs 12 siblings; CI=1.98-6.36, p=2e-6).

    “When we considered the proportion of individuals carrying at least one rare de novo CNV that also contains known genes (genic CNVs), the OR increased to 4.02 (50 in probands vs. 12 in siblings; CI =1.98-6.36, p=2 × 10−6).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Recurrent de novo CNVs at 16p11.2 are significantly associated with ASD (11 events, p=6e-23).

    “11 recurrent de novo CNVs at 16p11.2 (p= 6 × 10−23) are both highly significant”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rare de novo CNVs are more common in ASD probands from simplex families than in their unaffected siblings, with 5.8% of probands versus 1.7% of siblings carrying at least one such event (OR=3.55, CI=2.16-7.46, p=6.9e-6).

    “Overall 5.8% of probands (N=51 out of 872) had at least one rare de novo CNV compared with 1.7% of their unaffected siblings (N=15 out of 872) yielding an odds ratio (OR) of 3.55 (CI =2.16-7.46, p=6.9 × 10−6, Fisher's exact test)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Data from multiple studies provide compelling evidence for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin1 with ASD.

    “based on data from multiple studies, present compelling evidence for the association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin1”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The six recurrent regions in probands included 16p11.2, 7q11.23, 1q21.1, 15q13.2-q13.3, 16p13.2, and CDH13.

    “The 6 regions found in probands included 7 deletions and 4 duplications at chromosome 16p11.2, 4 duplications at 7q11.23 (the Williams-Beuren syndrome region), and 2 CNVs each at 1q21.1 (2 duplications), 15q13.2-q13.3 (1 deletion, 1 duplication), 16p13.2 (2 duplications), and disrupting the gene Cadherin 13 (CDH13) at 16q23.3 (5Mb deletion and an overlapping 34kb exonic deletion).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Rare de novo CNVs in probands included a greater number of genes, with a 16-fold increase overall and a 29-fold increase for deletions.

    “and to include a greater number of genes (16-fold increase in probands, and a 29-fold increase considering only deletions).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among failed de novo predictions, 82% were false positives in offspring and 18% were false negatives in parents.

    “82% of failures were false-positive predictions in offspring, 18% were false-negatives in parents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A total of 28,610 rare high-confidence CNVs were identified; 97 were classified as rare and likely de novo, and 83 were confirmed as rare de novo by qPCR.

    “A total of 28,610 rare, high-confidence CNVs were identified; 97 were classified as rare and likely de novo, and 83 events were confirmed to be rare de novo CNVs by qPCR in whole-blood DNA (Table S4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table S4

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    53% of de novo predictions based on at least 20 probes were confirmed, compared with 2.6% for predictions with fewer than 20 probes.

    “53% of de novo predictions based on ≥20 probes (N=94) were confirmed compared with 2.6% with <20 probes (N=430).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Probands carrying 7q11.23 duplications showed significantly more behavioral problems (ABC total) but less severe social and communication impairment during ADOS administration.

    “probands carrying 7q11.23 duplications showed significantly more behavioral problems (ABC total), but less severe social and communication impairment during ADOS administration.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The phenotypic data available on the SSC sample are highly reliable.

  • May combine two claims.

    Findingown data

    Rare transmitted CNVs were not present in greater numbers in affected individuals or in a greater proportion of probands versus siblings.

    “rare transmitted CNVs were not present in greater numbers in affected individuals or in a greater proportion of probands versus siblings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For females, the estimated effect of gene number on IQ was ten-fold less than for males and did not approach significance.

    “In contrast, for females the estimated effect was ten-fold less and did not approach significance”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The phenotypic data available on the SSC sample are highly reliable.

  • May combine two claims.

    Findingown data

    Neither sex nor the interaction of size and sex significantly predicted gene number within de novo CNVs.

    “Neither sex (p=0.20) nor the interaction of size and sex (p=0.06) was a significant predictor of gene number.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The phenotypic data available on the SSC sample are highly reliable.

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

    Findingown data

    BMI diminished as 16p11.2 copy number increased (β=−3.1 kg/m2 per extra copy, p=0.02).

    “BMI diminished as 16p11.2 copy number increased (estimated β=−3.1kg/m2 for each extra copy, p=0.02).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The phenotypic data available on the SSC sample are highly reliable.

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

    Findingown data

    Parents had prior knowledge of a 16p11.2 CNV in two instances (one de novo duplication and one transmitted deletion).

    “A review of medical histories obtained at the time of recruitment revealed that parents had prior knowledge of a 16p11.2 CNV in 2 instances (1 de novo duplication, 1 transmitted deletion).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    More siblings than probands carried maternally transmitted rare X-linked CNVs (14% vs 18%, OR=0.76, p=0.11), though the difference was not significant.

    “we found, contrary to expectations, that more siblings carried maternally transmitted rare CNVs than probands (14% probands vs. 18% siblings, OR=0.76, p=0.11), though this difference was not significant.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    A modest, non-significant excess of maternally transmitted autosomal singleton CNVs was found in probands (344 vs 303; OR=1.14; p=0.059 one-sided; p=0.12 two-sided).

    “we found a modest, non-significant excess of maternally transmitted CNVs in probands: 344 maternal autosomal singletons are transmitted to probands vs. 303 transmissions to siblings (OR= 1.14; p=0.059 one-sided; p=0.12 two-sided).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The eight regions with overlapping rare de novo and transmitted CNVs include five of the six recurrent intervals and three additional segments with one rare de novo event.

    “the 8 regions in probands showing overlapping rare de novo and rare transmitted CNVs include 5 of the 6 intervals with recurrent rare de novo variants, 1q21.1, 15q13.3, 16p13.2, 16p11.2, and 16q23.3 (Figure 4), and 3 additional genomic segments with 1 rare de novo event: 2p15, 6p11.2, and 17q12.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Recurrent de novo CNVs exceeding the significance threshold in the combined sample were also present at 7q11.23, 22q11.2, and NRXN1.

    “Recurrent de novo CNVs exceeding the significance threshold in the combined sample were also present at 7q11.23 (4 duplications; 0.003), 22q11.2 region (3 deletions and 2 duplications; 0.002 combined; 0.11 for deletions; 0.88 for duplications), and at the locus coding for the gene NRXN1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    16p13.2 and CDH13 are novel ASD loci, while 1q21 and 15q13.2-13.3 were previously implicated in neurodevelopmental disorders including ASD.

    “Two of these, 16p13.2 and the CDH13 locus, are novel ASD loci and two, 1q21, 15q13.2-13.3, have been previously implicated in neuro-developmental disorders including ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study confirms over-representation of rare de novo events in probands versus siblings with OR 3.55 for all variants and 4.02 for rare de novo genic variants.

    “We confirm an over-representation of rare de novo events in probands versus siblings with an odds ratio of 3.55 for all variants and 4.02 for rare de novo genic variants.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compelling evidence confirms the association of both 16p11.2 duplications and deletions.

    “Finally, we find compelling evidence confirming the association of both 16p11.2 duplications and deletions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    16p11.2 was the most frequent recurrent de novo CNV across all studies, with 19 probands (14 deletions, 5 duplications) showing extremely strong evidence for association with ASD.

    “The most frequent recurrent de novo CNV identified across all studies was 16p11.2 with 19 identified probands (14 deletions, 5 duplications) showing extremely strong evidence for association with ASD (2 × 10−55 combined; 5 × 10−29 for deletions; 2 × 10−5 for duplications).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The study clearly reproduced earlier findings and found new risk loci.

    “unambiguously replicating prior findings and identifying novel risk loci”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Twin studies establish a genetic contribution to ASD.

    “A genetic contribution is well established from twin studies (Bailey et al., 1995; Lichtenstein et al., 2010)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bailey et al., 1995 source

      Not checked in the free run.

    • cites Lichtenstein et al., 2010 source

      Not checked in the free run.

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

    Premisecitation

    Two of three studies confirmed a greater abundance of large de novo CNVs in simplex versus multiplex ASD families.

    “two of the three studies (Marshall et al., 2008; Pinto et al., 2010) have confirmed a greater abundance in simplex versus multiplex ASD families”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Marshall et al., 2008 source

      Not checked in the free run.

    • cites Pinto et al., 2010 source

      Not checked in the free run.

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

    Premisecitation

    Rare structural variants, both transmitted and de novo, show varying degrees of evidence for association with ASD.

    “Rare structural variants, both transmitted and de novo, also show varying degrees of evidence for association with ASD.”
    Quote in the paperNot a substantial claim

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

    Premiseown data

    The burden of rare de novo CNVs in simplex probands has ranged from 5.0% to 11%.

    “The burden of rare de novo CNVs in simplex probands (i.e. the percentage of individuals carrying ≥1 rare events) has ranged from 5.0-11% (Table S1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Table S1

      Not checked in the free run.

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

    Premisecitation

    The over-representation of large de novo CNVs in ASD has been replicated in studies of 60 to 393 simplex trios.

    “The over-representation of large de novo CNVs in ASD has been replicated in studies ranging from 60 to 393 simplex trios (Itsara et al., 2010; Marshall et al., 2008; Pinto et al., 2010)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Itsara et al., 2010 source

      Not checked in the free run.

    • cites Marshall et al., 2008 source

      Not checked in the free run.

    • cites Pinto et al., 2010 source

      Not checked in the free run.

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

    Premisecitation

    Large rare de novo CNVs were first reported to be more frequent in ASD probands from simplex families than in controls and than in multiplex probands.

    “Sebat et al. (2007) first noted that “large” (mean size of 2.3Mb), rare (<1% frequency in the general population), de novo events were more frequent in ASD probands from families with only a single affected child (i.e. simplex families) than in controls, as well as in comparison to probands from families with more than one affected individual (i.e. multiplex families).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sebat et al. (2007) source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Incomplete penetrance and affected siblings not sharing the same risk variant are common in ASD.

    “examples of incomplete penetrance (not all mutation carriers have disease), and affected siblings not sharing the same risk variant, have been the rule rather than the exception.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    16p11.2 deletions and duplications have been found in individuals with ASD, intellectual disability, seizure disorder, obesity, macrocephaly, and schizophrenia.

    “chromosome 16p11.2 deletions and duplications have been found in individuals with ASD and intellectual disability (ID) (Weiss et al., 2008), seizure disorder (Mefford et al., 2009), obesity (Bochukova et al., 2010), macrocephaly, and schizophrenia (McCarthy et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Weiss et al., 2008 source

      Not checked in the free run.

    • cites Mefford et al., 2009 source

      Not checked in the free run.

    • cites Bochukova et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Sensitivity for small de novo events was low for both arrays, and a pool of small de novo structural events was not considered in the analyses.

    “Of these 31 events only 13% (n=4) were identified by both groups, suggesting that the sensitivity for small de novo events was low for both arrays and that, as expected, there is a pool of small de novo structural events that were not considered in our analyses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Data from 1,124 families passed all quality control; 872 were quartets and 252 were trios.

    “Data from 1,124 families passed all quality control; 872 families were quartets that included two unaffected parents, a proband, and one unaffected sibling; 252 families were trios that included two unaffected parents and a proband”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The data do not support IQ or ASD severity as useful predictors for probands carrying large rare de novo risk variants in the SSC.

    “the data show a strong effect of large rare genic de novo CNVs on affected status, but do not support either IQ or ASD severity as useful predictors for probands carrying large rare de novo risk variants in the SSC”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The phenotypic data available on the SSC sample are highly reliable.

  • May combine two claims.

    Interpretationreasoning

    A second SSC cohort of similar composition and size will most likely confirm 7q11.23 and 16p11.2 and identify 2-3 additional significantly associated regions.

    “the most likely outcome of a second SSC cohort of similar composition and size to that reported here will be further confirmation of 7q11.23 and 16p11.2 and the identification of 2-3 additional regions of significant association.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    When restricted to rare transmitted CNVs, no significant difference was found between probands and siblings, suggesting that the excess burden in the SSC sample was entirely driven by rare de novo events.

    “when we again restricted the analysis of our sample to rare transmitted CNVs, by removing confirmed rare de novo events; there was no significant difference found between proband and siblings, suggesting that the excess burden in the SSC sample was entirely driven by rare de novo events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Duplications at 7q11.23 show very strong evidence for contribution to ASD, demonstrating genome-wide association in a case-control study for the first time.

    “we find very strong evidence for the contribution of duplications at 7q11.23, showing, for the first time., genome-wide association in a case-control study.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The reciprocal deletion at 7q11.23 causes Williams-Beuren syndrome, which features a highly social personality.

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

    Premisecitation

    Rare CNVs at 1q21.1 and 15q13.2-13.3 have been reported in developmental and neuropsychiatric syndromes, and deletions there occur in ASD, schizophrenia, and idiopathic epilepsy.

    “rare 1q21.1 and 15q13.2-13.3 CNVs have been identified in developmental and neuropsychiatric syndromes, with deletions found in ASD (Miller et al., 2009; Shen et al., 2010), schizophrenia (ISC, 2008; Stefansson et al., 2008), idiopathic epilepsy (Helbig et al., 2009)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Miller et al., 2009 source

      Not checked in the free run.

    • cites ISC, 2008

      Not checked in the free run.

    • cites Helbig et al., 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The reciprocal deletion of the 7q11.23 region causes a developmental syndrome that includes an empathic, gregarious, and highly social personality.

    “the reciprocal deletion results in a developmental syndrome characterized in part by an empathic, gregarious, and highly social personality (Pober, 2010)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Pober, 2010 source

      Not checked in the free run.

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

    Premisecitation

    Duplications of the 7q11.23 region have been reported before in developmental disorders, including autism spectrum disorder.

    “Duplications in this interval have previously been described in developmental disorders, including ASD (Berg et al., 2007; Van der Aa et al., 2009)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Berg et al., 2007 source

      Not checked in the free run.

    • cites Van der Aa et al., 2009 source

      Not checked in the free run.

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

    Premisecitation

    USP7 functions in oxidative stress response, histone modification, and chromatin remodeling regulation.

    “Ubiquitin Specific Peptidase 7 (USP7), which has been shown to have a role in oxidative stress response, histone modification and regulation of chromatin remodeling (Khoronenkova et al., 2010)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Khoronenkova et al., 2010

      Not checked in the free run.

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

    Premisecitation

    C16orf72 was recently identified in a schizophrenia CNV study.

    “C16orf72, coding for a protein of unknown function, recently identified in a schizophrenia CNV study (Levinson et al., 2011)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Levinson et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both C16orf72 and USP7 would represent novel ASD risk genes.

    “Both would represent novel ASD risk genes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The way the SSC sample was ascertained strengthened some findings and weakened others.

    “It is certain that the SSC sample ascertainment process enhanced certain findings and attenuated others.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    In 94.5% of quartet families, all members were hybridized and scanned together to reduce batch and technical variation.

    “824 or the 872 quartet families (94.5%) had all members hybridized and scanned simultaneously on the Illumina iScan in an effort to minimize batch effects and technical variation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The present report covers fewer than half of the Simons Simplex Collection.

    “this report considers less than half of the Simons Simplex Collection”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The rarity filter for de novo CNVs and the small sample limited testing of multi-hit hypotheses.

    “the filtering for rare de novo CNVs and the small sample size curtailed the assessment of multi-hit hypotheses”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The design reduced key confounds and retained enough power to detect association for recurrent de novo events.

    “the manner in which the design mitigated important confounds, and preserved sufficient power to detect association of recurrent de novo events, yielded clear benefits”
    Quote in the paperSubstantial claim

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

    Premisecitation

    For USP7, these processes, especially the ubiquitin pathway, have been linked to ASD pathogenesis before.

    “for the latter, these biological processes, and the ubiquitin pathway in particular, have been previously implicated in ASD pathogenesis (Glessner et al., 2009)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Glessner et al., 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Every family member was run on the same array version.

    “All members of each family were analyzed on the same array version: either the Illumina 1Mv1 (334 families) or Illumina 1Mv3 Duo (840 families) Bead-array.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Plink was used on genotyped samples to check sex, Mendelian errors, and cryptic relatedness; 11 families were removed.

    “Genotyped samples were analyzed using Plink (Purcell et al., 2007) to identify incorrect sex, Mendelian inconsistencies, and cryptic relatedness by assessing inheritance-by-descent (IBD); 11 families were removed as a result.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Purcell et al., 2007 source

      Not checked in the free run.

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

    Study design and conductown data

    CNV detection used three algorithms: PennCNV, QuantiSNP, and GNOSIS.

    “CNV detection was performed using three algorithms: 1) PennCNV Revision 220, 2) QuantiSNP v1.1, and 3) GNOSIS.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Five percent of samples failed and were rerun; repeated failures led to removal of 39 families.

    “5% of the samples failed and were rerun; 39 families were removed due to repeated failures.”
    Quote in the paperNot a substantial claim
54 of 54

  • The paper relies on this without support.

    The reciprocal deletion at 7q11.23 causes Williams-Beuren syndrome, which features a highly social personality.

    “where the reciprocal deletion causes Williams-Beuren syndrome, featuring a highly social personality”

  • The paper relies on this without support.

    The phenotypic data available on the SSC sample are highly reliable.

    “Given highly reliable phenotypic data and long standing interest in the role of sex in ASD risk and resilience”

  • The authors state this as an assumption.

    75% of de novo CNVs in probands confer risk.

    “we estimated that 75% of de novo CNVs in probands confer risk (67 de novo CNVs in probands – 16 de novo CNVs expected in siblings / 67 de novo CNVs in probands)”

  • The authors state this as an assumption.

    Recurrent de novo CNVs were assumed to be likely risk-associated and were included in that 75%.

    “assumed that recurrent de novo CNVs were most likely to be associated with risk and should be included within this 75%”

  • The authors state this as an assumption.

    Rare de novo CNVs seen in siblings were taken to be mostly non-risk and to form the null distribution.

    “the observed rare de novo CNVs in this group are assumed to be predominantly non-risk variants and consequently represent the null distribution.”

  • The authors state this as an assumption.

    In the calculation of C, g equals 1.

    “(In this calculation, due to the small number of observations, we assume that g equals 1.)”
6 of 6

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?

  • Several CNV studies identified structural changes in DNA, which contribute to the risk for ASD.

    “Several CNV studies (36, 43, 44) identified also structural changes in DNA, which contribute to the risk for ASD.”

    From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [44]

  • Genetic studies of de novo variants have consistently supported a female protective effect against ASD.

    “The possibility of a “female protective effect” (FPE) against ASD has been described extensively and has received consistent support from the results of genetic studies of de novo variants.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”

    From The female protective effect against autism spectrum disorder (2022) · cites this paper as [8]

  • Many types of ASD-associated de novo variants are observed more frequently in female cases.

    “Many types of ASD-associated de novo variants are observed more frequently in female cases.4, 5, 6, 7, 8, 9, 10, 11, 12, 13”

    From The female protective effect against autism spectrum disorder (2022) · cites this paper as [8]

  • The more ASD risk carried by a de novo variant class, the greater its overrepresentation among affected females.

    “In general, the more ASD risk carried by a de novo variant class, the greater its overrepresentation among affected females.8”

    From The female protective effect against autism spectrum disorder (2022) · cites this paper as [8]

  • On average, females accumulate more risk than males before being ascertained as ASD cases.

    “This suggests that, on average, females accumulate more risk than males before being ascertained as ASD cases.”

    From The female protective effect against autism spectrum disorder (2022) · cites this paper as [8]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Reported genic-CNV odds ratio is too low for the carrier counts

    Major

    The study compares 872 probands with 872 siblings. With 50 carriers versus 12, the carrier-count ratio is 4.17, and accounting for noncarriers gives an odds ratio of about 4.36-not the reported 4.02.

    Reported 4.02 · recomputed 4.166667

  • Combined-study de novo CNV total changes without an explained restriction

    Minor

    The combined analysis reports 228 confirmed rare de novo CNVs, but its subsequent estimate starts from a total of 219 confirmed de novo events. No restriction accounting for the nine-event difference is stated.

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Authors
Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D., Chu, S. H., Moreau, M. P., Gupta, A. R., Thomson, S. A., Mason, C. E., Bilguvar, K., Celestino-Soper, P. B. S., Choi, M., Crawford, E. L., Davis, L., Davis Wright, N. R., Dhodapkar, R. M., DiCola, M., DiLullo, N. M., Fernandez, T. V., Fielding-Singh, V., Fishman, D. O., Frahm, S., Garagaloyan, R., Goh, G. S., Kammela, S., Klei, L., Lowe, J. K., Lund, S. C., McGrew, A. D., Meyer, K. A., Moffat, W. J., Murdoch, J. D., O'Roak, B. J., Ober, G. T., Pottenger, R. S., Raubeson, M. J., Song, Y., Wang, Q., Yaspan, B. L., Yu, T. W., Yurkiewicz, I. R., Beaudet, A. L., Cantor, R. M., Curland, M., Grice, D. E., Günel, M., Lifton, R. P., Mane, S. M., Martin, D. M., Shaw, C. A., Sheldon, M., Tischfield, J. A., Walsh, C. A., Morrow, E. M., Ledbetter, D. H., Fombonne, E., Lord, C., Martin, C. L., Brooks, A. I., Sutcliffe, J. S., Cook, E. H., Geschwind, D., Roeder, K., Devlin, B., & State, M. W.
Affiliations
  • Yale University (US)
  • University of California, Los Angeles (US)
  • Carnegie Mellon University (US)
  • Rutgers, The State University of New Jersey (US)
  • Vanderbilt University (US)
  • Weill Cornell Medicine (US)
  • Howard Hughes Medical Institute (US)
  • University of Illinois Chicago (US)
  • University of Pittsburgh (US)
  • University of Michigan (US)
  • Princeton University (US)
  • Boston Children's Hospital (US)
  • Baylor College of Medicine (US)
  • New York State Psychiatric Institute (US)
  • Brown University (US)
  • Geisinger Health System (US)
  • Montreal Children's Hospital (CA)
  • Emory University (US)
Corresponding author
State, Matthew W.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2011-06
Volume
70
Issue
5
Pages
863-885
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2011.05.002
PMC
PMC3939065
OpenAlex
W2012203722
Cited by
1,263
References
75
Citations by year
2026: 19 · 2025: 39 · 2024: 42 · 2023: 44 · 2022: 51 · 2021: 81 · 2020: 72 · 2019: 69 · 2018: 74 · 2017: 86 · 2016: 87 · 2015: 155 · 2014: 143 · 2013: 137 · 2012: 127
FWCI
87.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • Simons Foundation
  • National Institute of Mental Health (K23MH080954, K08MH087639, R01MH057881, T32MH065215, R25MH077823)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
autism spectrum disorder, copy number variation, de novo duplication, Williams syndrome, USP7, CDH13, 16p11.2, NRXN1, genetic risk, genome-wide association study
MeSH terms
Ubiquitin-Specific Peptidase 7, Adolescent, Calcium-Binding Proteins, Child, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 7, Family Health, Female, Genotype, Humans, Male, Nerve Tissue Proteins, Phenotype, Proteins, Cell Adhesion Molecules, Neuronal, Cadherins, Williams Syndrome, Neural Cell Adhesion Molecules, Oligonucleotide Array Sequence Analysis, Gene Duplication, Gene Expression Profiling, Siblings, Chromosomes, Human, X, Ubiquitin Thiolesterase, Genome-Wide Association Study, 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 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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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