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Cited by 634Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomic variations and chromosomal abnormalities

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Open access
Leblond, Claire S., Nava, Caroline, Polge, Anne, Gauthier, Julie, Huguet, Guillaume, Lumbroso, Serge, Giuliano, Fabienne, Stordeur, Coline +52 more·2014·PLoS Genetics
DOI 10.1371/journal.pgen.1004580PMC PMC4154644
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Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

AI snapshot

Written from the paper’s full text.

TL;DR

This meta-analysis plus new screening found SHANK copy-number and truncating coding-sequence variants in ~1% of patients with ASD, with a gene-specific gradient of cognitive severity: SHANK1 in normal-IQ autism, SHANK2 in mild ID, and SHANK3 in moderate-to-profound ID. SHANK3 mutations were the most frequent and clinically relevant, accounting for more than 1 in 50 cases with ASD plus intellectual disability.

Key findings

  • SHANK1 mutations were rare: CNVs in 0.04% of ASD cases (2/5,657) versus 0/19,163 controls (meta-analysis fixed-effect P=0.19, OR=2.73, 95% CI 0.60–12.48), and no truncating coding-sequence variants were found (0/760 ASD, 0/492 controls). Damaging missense variants were more frequent in ASD (3.16% vs 1.02%, P=0.012, OR=3.17), but this did not survive Bonferroni correction; carriers had normal IQ (mean IQ=107) and ASD.
  • SHANK2 mutations were associated with mild ID: CNVs in 0.05% of ASD cases (3/5,657) versus 0/19,163 controls (P=0.076, OR=3.76), truncating coding-sequence variants in 0.12% (1/851 ASD vs 0/1,090 controls), and damaging missense variants in 4.58% vs 2.66% (P=0.025, OR=1.76). Carriers had mild to moderate ID (mean IQ=62±17).
  • SHANK3 mutations were most frequent and severe: CNVs in 0.18% of ASD cases (10/5,657) versus 0.01% of controls (2/19,163; P=0.019, OR=4.05), and truncating coding-sequence variants in 0.51% (11/2,147 ASD vs 0/1,031 controls; P=0.29, OR=2.85). In ASD with ID (IQ<70), de novo or truncating SHANK3 mutations reached 2.12% (CNVs 6/917=0.65%; coding-sequence 9/611=1.47%), versus 0% in ASD without ID and 0.01% in controls; carriers had moderate to severe/profound ID (mean IQ=31±8).
  • Across genes, truncating/CNV mutations were present in ~1% of ASD cases: SHANK1 0.04%, SHANK2 0.17%, SHANK3 0.69%, with a gradient from normal IQ (SHANK1) to mild ID (SHANK2) to moderate-to-profound ID (SHANK3).

Methods

  • Meta-analysis of SHANK copy-number variants (5,657 ASD cases and 19,163 controls from 11 studies, including this one) and coding-sequence variants (760–2,147 ASD cases and 492–1,090 controls depending on gene, from 10 studies, including this one). New screening included 46 ASD cases/454 controls for CNVs, 251 ASD cases/492 controls for SHANK1 exons, and 429 ASD cases/80 controls added to SHANK3 coding-sequence screening; de novo or truncating mutation carriers underwent extended clinical investigation.
  • ASD diagnosis used ADI-R, and in some cases ADOS or DISCO-10; IQ was measured with age-appropriate Wechsler scales, Raven’s Standard Progressive Matrices, or PPVT, plus systematic physical examination for dysmorphic and neurological features.
  • Statistical analysis used two-sided Fisher’s exact tests, Bonferroni correction for 12 tests (corrected α=0.0042), inverse-variance fixed- and random-effects meta-analysis, heterogeneity statistics (Q, I², Tau²), and power calculations; SHANK2 and SHANK3 reference sequences were corrected before screening.

Limitations

  • The paper states that inherited SHANK1 and SHANK2 variant associations did not survive Bonferroni correction, and the study was underpowered for low-effect-size inherited variants: power to detect an OR of 1.5 for SHANK1, SHANK2, and SHANK3 missense inherited damaging variants was 8%, 34%, and 17%, respectively; larger IQ-stratified cohorts are needed.
  • The paper notes that only non-synonymous mutations in known exons were screened; splicing isoforms, synonymous mutations, and regulatory variants were rarely reported, and whole-exome sequencing studies were excluded because of very low SHANK3 coverage. Some father DNA was unavailable for two SHANK3 truncating cases, two SHANK2 deletion patients were not included in prevalence calculations because the exact number screened was unavailable, and two unvalidated SHANK3 control deletions should be interpreted with caution.
  • Evident from the text: the meta-analysis relied on combining heterogeneous published cohorts, and although the authors contacted corresponding authors to avoid overlapping samples, control data for SHANK1 coding variants were incomplete in one prior study and were excluded from that analysis.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pgen.1004580

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    SHANK3 mutations were present in up to 2.12% of cases with moderate to profound intellectual disability.

    “mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability”
    Quote in the paperSubstantial claim
  • Findingown data

    Rare SHANK2 coding-sequence variants predicted as damaging were observed in 4.58% of patients with ASD compared with 2.66% of controls (P = 0.025, OR = 1.76, 95% CI = 1.05-2.97).

    “we observed rare coding-sequence variants predicted as damaging in 4.58% of the patients with ASD compared with 2.66% of the controls (Fisher's exact test two-sided, P = 0.025, OR = 1.76, 95% CI = 1.05–2.97).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rare coding-sequence variants predicted as damaging by polyphen-2 are functionally deleterious.
  • Findingown data

    SHANK2 deletions were found in 0.05% of patients with ASD and never in controls (P = 0.076, OR = 3.76, 95% CI = 0.87-16.25).

    “SHANK2 deletions were found in 0.05% (n = 3/5 657) of patients with ASD, and never in controls (n = 0/19 163; Meta-analysis – Inverse variance method - fixed effect model, P = 0.076, OR = 3.76, 95% CI = 0.87–16.25)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Individuals carrying a SHANK2 de novo deletion were diagnosed with autistic disorder or PDD-NOS in combination with mild to moderate ID (mean IQ = 62±17).

    “The individuals carrying a SHANK2 de novo deletion were diagnosed with autistic disorder or pervasive developmental disorder not otherwise specified (PDD-NOS) in combination with mild to moderate ID (mean IQ = 62±17)”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.
  • Findingown data

    An enrichment of truncating mutations in exon 21a of SHANK3 was observed.

    “We observed an enrichment of truncating mutations in exon 21a of SHANK3.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 26
  • May combine two claims. 26
  • The quote only partly states this claim. 2

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

    Findingown data

    One patient (AU029) carrying a de novo SHANK3 deletion of 1.5 Mb was identified.

    “we identified one patient (AU029) carrying a de novo SHANK3 deletion of 1.5 Mb (Figure S4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Individuals carrying a SHANK2 de novo deletion displayed minor signs of dysmorphism and abnormal neurological examination.

    “They also displayed minor signs of dysmorphism (broad nasal bridge, thin upper lip, pointed chin, clinodactyly) and abnormal neurological examination (Table 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.

  • May combine two claims.

    Findingown data

    The prevalence of truncating SHANK2 coding-sequence variants was 0.12% in patients with ASD, and such variants were not found in any of the 1,090 controls.

    “the prevalence of truncating SHANK2 coding-sequence variants was 0.12% in patients with ASD (n = 1/851), and such variants were not found in any of the 1 090 controls”
    Quote in the paperSubstantial claim

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

    Findingown data

    Patient RDB_30769 carried a de novo deletion of 1.8 Mb encompassing SHANK2.

    “The second patient (RDB_30769) carried a de novo deletion of 1.8 Mb encompassing SHANK2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Individuals carrying a SHANK2 de novo deletion displayed early signs of developmental delay, mild motor delay and significant language delay.

    “They displayed early signs of developmental delay, mild motor delay and significant language delay.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.

  • May combine two claims.

    Findingown data

    The individual carrying the de novo truncating SHANK2 mutation R841X had a normal IQ and was diagnosed with ASD without any developmental delays or dysmorphic features.

    “The individual carrying the de novo truncating mutation R841X (SK 0441-003) had a normal IQ and diagnosed with ASD without any developmental delays or dysmorphic features.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SHANK1 mutations/deletions were rare, detected in 0.04% of patients with ASD and never in controls.

    “mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism”
    • Also stated in: § SHANK1 in ASD · plain
      “deletions disrupting SHANK1 were detected in 0.04% (n = 2/5 657) of patients with ASD and were never found in 19 163 controls (Meta-analysis – Inverse variance method - fixed effect model P = 0.19, OR = 2.73, 95% CI = 0.60–12.48)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When all mutation screenings were included, truncating SHANK3 coding-sequence variants were found in 0.51% of patients and were not found in 1,031 controls (P = 0.29, OR = 2.85, 95% CI = 0.41-19.96).

    “When all mutation screenings were included, truncating SHANK3 coding-sequence variants were found in 0.51% of the patients (n = 11/2 147) and were not found in 1031 controls (meta-analysis – inverse variance method - fixed effect model, P = 0.29, OR = 2.85, 95% CI = 0.41–19.96)”
    Quote in the paperSubstantial claim

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

    Findingcitation

    No de novo truncating SHANK1 mutation sequences were identified.

    “As for the SHANK1 mutation screening by Sato et al. (2012), no de novo truncating mutation sequences were identified.”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    In three families from France and Canada, the SHANK3 deletions originated from a balanced translocation present in a healthy parent.

    “In three families from France and Canada, the SHANK3 deletions originated from a balanced translocation present in a healthy parent [6], [13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] CM Durand, 2007, Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders, Nat Genet source

      Not checked in the free run.

    • cites [13] R Moessner, 2007, Contribution of SHANK3 mutations to autism spectrum disorder, Am J Hum Genet source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The boy carrying the L1142Vfs*153 mutation was non-verbal, showed a global developmental delay with neonatal hypotonia and typical dysmorphic features of Phelan-McDermid syndrome, and developed generalized epilepsy at the age of 10 years.

    “For example, the boy carrying the L1142Vfs*153 mutation was non-verbal, showed a global developmental delay with neonatal hypotonia and typical dysmorphic features of Phelan-McDermid syndrome, including wide nasal bridge, pointed chin, deep-set eyes, flat mid-face, large ears, long eyelashes, bulbous nose, and high-arched palate (Table 2). He also developed generalized epilepsy at the age of 10 y”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    In two families, a sibling carried the reciprocal SHANK3 duplication.

    “Interestingly, in two families, a sibling carried the reciprocal SHANK3 duplication.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] CM Durand, 2007, Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders, Nat Genet source

      Not checked in the free run.

    • cites [13] R Moessner, 2007, Contribution of SHANK3 mutations to autism spectrum disorder, Am J Hum Genet source

      Not checked in the free run.

  • The quote only partly states this claim.

    Findingown data

    SHANK2 mutations were present in 0.17% of patients with ASD.

    “mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability”
    Quote in the paperSubstantial claim

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

    Findingown data

    In the damaging missense category, two SHANK3 variants (P141A and Q321R) were de novo.

    “In the damaging missense category, two SHANK3 (P141A & Q321R) were de novo.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Patient AUN_006 has a deletion breakpoint within intron 8 of SHANK3 leading to loss of SHANK3 exons 9 to 22, ACR and RABL2B.

    “For patient AUN_006, the deletion breakpoint is located within intron 8 of SHANK3 and leads to the loss of SHANK3 (exons 9 to 22), ACR and RABL2B.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    No SHANK1 duplications were found.

    “No SHANK1 duplications were found.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    All truncating SHANK variants were de novo (for three, the DNA of one parent was not available).

    “All truncating SHANK variants were de novo (for three, the DNA of one parent was not available).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    No SHANK2 duplications were reported.

    “No SHANK2 duplications were reported.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Patient AUN_007 has a deletion covering exon 22 of SHANK3 and exons 1 to 3 of ACR.

    “For the second patient AUN_007, the deletion covers the exon 22 of SHANK3 and exons 1 to 3 of ACR.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Two patients with a SHANK2 de novo deletion were identified.

    “We identified two patients with a SHANK2 de novo deletion (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All SHANK2 deletions were de novo and disrupted coding exons.

    “All deletions were de novo and disrupted coding exons.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The boy carrying the de novo truncating mutation S1202Cfs*81 was verbal and had moderate ID, with clinical examination considered in the normal range and no significant dysmorphic features.

    “By contrast, the boy carrying the de novo truncating mutation S1202Cfs*81 was verbal and had moderate ID. Although reduced in quality by the opposition of the patient, the clinical examination was considered in the normal range with no significant dysmorphic features.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In a screen of 429 patients with ASD for all coding exons of SHANK3, 8 patients carrying heterozygous truncating mutations were found, including 6 that appeared de novo.

    “We screened 429 patients with ASD for all coding exons of SHANK3 and found 8 patients carrying heterozygous truncating mutations (Figure 1 and 3, Figure S5, Table 1, Table S4, S5, S6, S7 and Table S11), including 6 that appeared de novo in the probands.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SHANK mutations were detected in the whole spectrum of ASD with a gradient of severity in cognitive impairment.

    “Mutations of the SHANK genes were detected in the whole spectrum of ASD with a gradient of severity in cognitive impairment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The cohorts included in the meta-analysis are representative of the whole ASD population.

  • May combine two claims.

    Findingown data

    A total of 760-2147 patients and 492-1090 controls were included in the analysis (SHANK1: 760 patients and 492 controls; SHANK2: 851 patients and 1090 controls; SHANK3: 2147 patients and 1031 controls).

    “Taken together, a total of 760–2 147 patients and 492–1 090 controls were included in the analysis (SHANK1: 760 patients and 492 controls; SHANK2: 851 patients and 1 090 controls; SHANK3: 2 147 patients and 1 031 controls).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The number of non-overlapping samples from five studies was 1866 patients with ASD and 15122 controls, and the total number of non-overlapping samples used in the meta-analysis was 5657 patients with ASD and 19163 controls.

    “The number of non-overlapping samples from these five studies was 1 866 patients with ASD and 15 122 controls, and the total number of non-overlapping samples used in the meta-analysis was 5 657 patients with ASD and 19 163 controls.”
    Quote in the paperSubstantial claim

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

    Findingown data

    In our cohort, we did not find synonymous mutations located at alternative splicing sites.

    “In our cohort, we did not find synonymous mutations located at alternative splicing sites”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The majority of mutations detected in this study were located in the exonic region of SHANK3 showing a very low coverage.

    “the majority of the mutations detected in our study were located in the exonic region of SHANK3 showing a very low coverage (Figure S3)”
    Quote in the paperSubstantial claim

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

    Interpretationcitation

    Sex differences might modulate the SHANK1 phenotype, since females carrying an inherited SHANK1 deletion exhibited anxiety and shyness but did not fulfill criteria for ASD.

    “Interestingly, sex differences might modulate the phenotype since females carrying an inherited SHANK1 deletion exhibited anxiety and shyness, but did not fulfill criteria for ASD [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] D Sato, 2012, SHANK1 Deletions in Males with Autism Spectrum Disorder, Am J Hum Genet source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment.

    “In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment.”
    • Also stated in: § Cohorts used for the meta-analysis of SHANK mutations · plain
      “Mutations in SHANK1-3 are associated with a gradient of severity in cognitive impairment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The clinical phenotype associated with SHANK mutations is primarily attributable to the SHANK gene affected rather than to other genetic or environmental factors.

  • May combine two claims.

    Study design and conductnone given

    The power achieved to observe the statistical difference between patients and controls for SHANK1 and SHANK2 damaging missense variants was 69% and 59%.

    “The power achieved to observe the statistical difference between patients and controls for SHANK1 and SHANK2 damaging missense variants was 69% and 59%.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    SHANK genes code for large synaptic scaffold proteins of the post-synaptic density.

    “Here, we focused on the three SHANK genes, which code for large synaptic scaffold proteins of the post-synaptic density [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] AM Grabrucker, 2011, Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies, Trends Cell Biol source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationown data

    SHANK2 mutations were associated with mild intellectual disability.

    “mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Male individuals carrying SHANK1 deletions do not present with language delay or ID and are diagnosed with normal IQ ASD or Asperger syndrome.

    “male individuals carrying SHANK1 deletions do not present with language delay or ID and are diagnosed with normal IQ ASD or Asperger syndrome [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] D Sato, 2012, SHANK1 Deletions in Males with Autism Spectrum Disorder, Am J Hum Genet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    For SHANK2 and SHANK3 mutations, it is expected that affected neurons will have a reduced total number of dendritic spines and synapses.

    “For SHANK2 and SHANK3 mutations, it is expected that affected neurons will have a reduced total number of dendritic spines and synapses.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    SHANK1 mutations might lead to an immature neuronal network with a reduced number of large spine heads.

    “SHANK1 mutations might rather lead to an immature neuronal network with a reduced number of large spine heads.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The reduction in mature glutamatergic synapses is expected to affect cognitive functions.

    “The reduction in mature glutamatergic synapses is expected to affect cognitive functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The difference in severity of cognitive impairment between SHANK3 and SHANK2 mutations is in agreement with the observation that SHANK3 mutations are highly penetrant and that for SHANK2 additional genetic/epigenetic factors might be necessary.

    “This difference in severity of cognitive impairment is in agreement with the observation that SHANK3 mutations are highly penetrant (to our knowledge only one validated SHANK3 deletion has been reported to be inherited from a mother with moderate ID [45]), while for SHANK2, additional genetic/epigenetic factors might be necessary to develop ASD [18], [19], [46].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Previous functional studies have shown that inherited variants are associated with a statistically significant reduction in the density of synapses, although not as severe as the reduction caused by de novo or truncating mutations.

    “Previous functional studies have shown that inherited variants are associated with a statistically significant reduction in the density of synapses, although not as severe as the reduction caused by the de novo or truncating mutations [6], [18], [42]–[44].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] CM Durand, 2007, Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders, Nat Genet source

      Not checked in the free run.

    • cites [18] CS Leblond, 2012, Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders, PLoS Genet source

      Not checked in the free run.

    • cites [42]–[44]

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    The two SHANK3 deletions reported by Glessner et al. (2009) in control subjects have not been validated and should be interpreted with caution.

    “The two SHANK3 deletions reported by Glessner et al. (2009) [34] in control subjects have not been validated and should be interpreted with caution.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] JT Glessner, 2009, Autism genome-wide copy number variation reveals ubiquitin and neuronal genes, Nature source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    To ensure that the cohorts were constituted of independent and unrelated cases and controls, the authors contacted the corresponding authors of each study.

    “To ensure that the cohorts were constituted of independent and unrelated cases and controls, we contacted the corresponding authors of each study.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Some inherited SHANK mutations might contribute to the development of ASD, although present in healthy parents.

    “Together, these genetic and functional data suggest that, although present in healthy parents, some inherited SHANK mutations might contribute to the development of ASD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    In summary, our genetic and clinical findings provide additional support for considering SHANK mutations in a broad spectrum of patients with ASD.

    “In summary, our genetic and clinical findings provide additional support for considering SHANK mutations in a broad spectrum of patients with ASD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The cohorts included in the meta-analysis are representative of the whole ASD population.

  • May combine two claims.

    Interpretationreasoning

    Females who are carriers of a SHANK1 deletion seem to be protected against ASD, suggesting that X-linked genes escaping X-inactivation and/or hormonal factors could buffer this type of synaptic alterations.

    “females who are carrier of a SHANK1 deletion seem to be protected against ASD suggesting that X-linked genes escaping the X-inactivation process and/or hormonal factors could buffer this type of synaptic alterations.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To avoid population stratification bias in the calculation of the odds ratio, studies without a control group were excluded.

    “To avoid population stratification bias in the calculation of the odds ratio (OR), studies without a control group were excluded (i.e. Boccuto et al. 2012 and Bremer et al. 2012) (Figure 2, 3, and Table 1).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    It has been proposed that abnormal SHANK levels at the synapse might result in the mislocalization, de-clustering and/or functional impairment of several other crucial synaptic proteins such as cytoskeletal regulators and/or neurotransmitter receptors.

    “It has been proposed that abnormal SHANK levels at the synapse might result in the mislocalization, de-clustering and/or functional impairment of several other crucial synaptic proteins such as cytoskeletal regulators and/or neurotransmitter receptors [12] (Table 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] AM Grabrucker, 2011, Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies, Trends Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    For SHANK1, Sato et al. (2012) did not screen for all SHANK1 exons in the controls, so these controls were not included in the analysis.

    “For SHANK1, there are two studies (Sato et al. (2012) [19] and this study), but Sato et al. (2012) [19] did not screen for all SHANK1 exons in the controls. Therefore these controls were not included here.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] D Sato, 2012, SHANK1 Deletions in Males with Autism Spectrum Disorder, Am J Hum Genet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    For SHANK1 mutations, it is expected that the number of dendrites and glutamatergic synapses will not be dramatically affected (if at all).

    “For SHANK1 mutations, it is expected that the number of dendrites and glutamatergic synapses will not be dramatically affected (if at all).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Other genes involved in the same synaptic pathway, including neurexin and neuroligin genes, appear to be associated with a variety of neuropsychiatric disorders.

    “other genes involved in the same synaptic pathway, including neurexin and neuroligin genes, appear to be associated with a variety of neuropsychiatric disorders [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] TC Sudhof, 2008, Neuroligins and neurexins link synaptic function to cognitive disease, Nature source

      Not checked in the free run.

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

    Study design and conductnone given

    The frequencies of SHANK mutations have been calculated including only unrelated cases and controls.

    “The frequencies of SHANK mutations have been calculated including only unrelated cases and controls.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Because of the very low coverage of whole exome sequencing, mutation screening performed using this approach was excluded.

    “Because of the very low coverage of whole exome sequencing (Figure S3 and Text S1), we excluded mutation screening performed using this approach.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    For controls, the two SHANK3 deletions reported by Glessner et al. (2009) among 2519 individuals were not validated and thus should be regarded with caution.

    “For controls, the two SHANK3 deletions reported by Glessner et al. (2009) among 2 519 individuals, were not validated and thus should be regarded with caution.”
    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 conductnone given

    For patients with ASD, only copy-number variants validated by an independent method were included in the analysis.

    “For patients with ASD, only copy-number variants validated by an independent method were included in the analysis.”
    Quote in the paperSubstantial claim
53 of 53

  • The paper relies on this without support.

    The published studies included in the meta-analysis used comparable methods for detecting SHANK variants and comparable ASD/control ascertainment.

    “This meta-analysis included the published data from 14 studies in addition to a new screening of SHANK copy-number variants and coding sequence variants.”

  • The paper relies on this without support.

    Rare coding-sequence variants predicted as damaging by polyphen-2 are functionally deleterious.

    “rare inherited coding-sequence variants predicted as damaging were, however, more frequent in patients with ASD than in controls”

  • The paper relies on this without support.

    The clinical phenotype associated with SHANK mutations is primarily attributable to the SHANK gene affected rather than to other genetic or environmental factors.

    “Mutations in SHANK1-3 are associated with a gradient of severity in cognitive impairment.”

  • The paper relies on this without support.

    Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.

    “When possible, the patients carrying truncating mutations altering SHANK genes underwent further clinical investigations (Table 2 & S7).”

  • The paper relies on this without support.

    The cohorts included in the meta-analysis are representative of the whole ASD population.

    “In the whole spectrum of ASD, we estimated that 0.04%, 0.17% and 0.69% of cases with ASD had heterozygous truncating mutations in SHANK1, SHANK2 or SHANK3, respectively (Table 1).”

  • The paper relies on this without support.

    The control groups included in the meta-analysis are representative of the general population without ASD.

    “0.01% in controls”

  • The paper relies on this without support.

    The SHANK mutations classified as truncating or damaging are pathogenic.

    “we estimated that 0.04%, 0.17% and 0.69% of cases with ASD had heterozygous truncating mutations in SHANK1, SHANK2 or SHANK3, respectively (Table 1).”
7 of 7

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Authors
Leblond, C. S., Nava, C., Polge, A., Gauthier, J., Huguet, G., Lumbroso, S., Giuliano, F., Stordeur, C., Depienne, C., Mouzat, K., Pinto, D., Howe, J., Lemière, N., Durand, C. M., Guibert, J., Ey, E., Toro, R., Peyre, H., Mathieu, A., Amsellem, F., Rastam, M., Gillberg, I. C., Rappold, G. A., Holt, R., Monaco, A. P., Maestrini, E., Galan, P., Heron, D., Jacquette, A., Afenjar, A., Rastetter, A., Brice, A., Devillard, F., Assouline, B., Laffargue, F., Lespinasse, J., Chiesa, J., Rivier, F., Bonneau, D., Regnault, B., Zelenika, D., Delepine, M., Lathrop, M., Sanlaville, D., Schluth-Bolard, C., Edery, P., Perrin, L., Tabet, A. C., Schmeisser, M. J., Boeckers, T. M., Coleman, M., Sato, D., Szatmari, P., Scherer, S. W., Rouleau, G. A., Betancur, C., Leboyer, M., Gillberg, C., Delorme, R., & Bourgeron, T.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Centre Hospitalier Universitaire de Nîmes (FR)
  • Centre Hospitalier Universitaire Sainte-Justine (CA)
  • Centre Hospitalier Universitaire de Nice (FR)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Toronto (CA)
  • Institut Pasteur (FR)
  • University of Gothenburg (SE)
  • Heidelberg University (DE)
  • Centre for Human Genetics (GB)
  • University of Bologna (IT)
  • Conservatoire National des Arts et Métiers (FR)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Hôpital Armand-Trousseau (FR)
  • Hôpital Couple Enfant (FR)
  • Centre Hospitalier Universitaire de Clermont-Ferrand (FR)
  • Inserm (FR)
  • Lyon 1 Université (FR)
  • Universität Ulm (DE)
  • Montreal Neurological Institute and Hospital (CA)
  • University College London (GB)
Corresponding author
Bourgeron, Thomas
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2014-09-04
Volume
10
Issue
9
Pages
e1004580
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1004580
PMC
PMC4154644
OpenAlex
W2141041915
Semantic Scholar
765f93019a616c818b4b4525f202bb4aeb20152c
Cited by
630
References
58
Citations by year
2026: 30 · 2025: 38 · 2024: 72 · 2023: 61 · 2022: 65 · 2021: 62 · 2020: 51 · 2019: 50 · 2018: 58 · 2017: 57 · 2016: 43 · 2015: 39 · 2014: 4
FWCI
6.30
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship@McGill (McGill) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Lund University Publications (Lund University) (submittedVersion, other-oa)
Funders
  • Fondation FondaMental
  • Fondation Cognacq-Jay
  • Fondation Orange
  • Deutsche Forschungsgemeinschaft
  • Agence Nationale de la Recherche (ANR-08-MNPS-0037)
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
  • Université Paris Diderot
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, SHANK3, Shank2, Shank1, copy number variation, truncating mutations, intellectual disability, cognitive impairment severity, de novo mutations, postsynaptic density, glutamatergic synapses, dendritic spines, mutation detection
MeSH terms
Child, Child Development Disorders, Pervasive, Cognition, Cognition Disorders, Female, Humans, Male, Intellectual Disability, Mutation, Nerve Tissue Proteins, Neurons, Synapses, Case-Control Studies, DNA Copy Number Variations

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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 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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