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

The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index; none of the 37 sources its claims cite is checked for support yet.

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, Depienne, Christel, Mouzat, Kevin, Pinto, Dalila, Howe, Jennifer, Lemière, Nathalie, Durand, Christelle M., Guibert, Jessica, Ey, Elodie, Toro, Roberto, Peyre, Hugo, Mathieu, Alexandre, Amsellem, Frédérique, Rastam, Maria, Gillberg, I. Carina, Rappold, Gudrun A., Holt, Richard, Monaco, Anthony P., Maestrini, Elena, Galan, Pilar, Heron, Delphine, Jacquette, Aurélia, Afenjar, Alexandra, Rastetter, Agnès, Brice, Alexis, Devillard, Françoise, Assouline, Brigitte, Laffargue, Fanny, Lespinasse, James, Chiesa, Jean, Rivier, François, Bonneau, Dominique, Regnault, Beatrice, Zelenika, Diana, Delepine, Marc, Lathrop, Mark, Sanlaville, Damien, Schluth-Bolard, Caroline, Edery, Patrick, Perrin, Laurence, Tabet, Anne Claude, Schmeisser, Michael J., Boeckers, Tobias M., Coleman, Mary, Sato, Daisuke, Szatmari, Peter, Scherer, Stephen W., Rouleau, Guy A., Betancur, Catalina, Leboyer, Marion, Gillberg, Christopher, Delorme, Richard, Bourgeron, Thomas·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.

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Registry

Crossref · 10.1371/journal.pgen.1004580

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK2 in ASD
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Rests on an assumption: Rare coding-sequence variants predicted as damaging by polyphen-2 are functionally deleterious.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK2 in ASD
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Rests on an assumption: Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 prof”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Abstract
Load-bearingStrength:plain· not yet calibratedn = 5,657
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Rests on an assumption: The published studies included in the meta-analysis used comparable methods for detecting SHANK variants and comparable ASD/control ascertainment.
In the paper
“In the Canadian family, the elder sister carrying the SHANK3 duplication was diagnosed with attention-deficit/hyperactivity disorder (ADHD) and developmental delay [13].”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK3 in ASD
What the sources say
- Not checked yetcites [13] R Moessner, 2007, Contribution of SHANK3 mutations to autism spectrum disorder, Am J Hum Genet source
Strength:plain· not yet calibratedSingle case
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes

Show all 56 claims

Probably not a substantial claim. 26
It may state two separate claims as one. 26
The quote only partly states this claim. 2

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“They also displayed minor signs of dysmorphism (broad nasal bridge, thin upper lip, pointed chin, clinodactyly) and abnormal neurological examination (Table 2).”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK2 in ASD
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“They displayed early signs of developmental delay, mild motor delay and significant language delay.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK2 in ASD
Strength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Patients carrying de novo or truncating SHANK mutations who underwent clinical investigation are representative of all individuals with such mutations.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Abstract
Load-bearingStrength:plain· not yet calibratedn = 2
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In three families from France and Canada, the SHANK3 deletions originated from a balanced translocation present in a healthy parent [6], [13].”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK3 in ASD
What the sources say
- Not checked yetcites [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 yetcites [13] R Moessner, 2007, Contribution of SHANK3 mutations to autism spectrum disorder, Am J Hum Genet source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedn = 3
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, in two families, a sibling carried the reciprocal SHANK3 duplication.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK3 in ASD
What the sources say
- Not checked yetcites [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 yetcites [13] R Moessner, 2007, Contribution of SHANK3 mutations to autism spectrum disorder, Am J Hum Genet source
Strength:plain· not yet calibratedn = 2
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mutations of the SHANK genes were detected in the whole spectrum of ASD with a gradient of severity in cognitive impairment.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Discussion
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: The cohorts included in the meta-analysis are representative of the whole ASD population.
In the paper
“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].”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > SHANK1 in ASD
What the sources say
- Not checked yetcites [19] D Sato, 2012, SHANK1 Deletions in Males with Autism Spectrum Disorder, Am J Hum Genet source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Abstract
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibratedn = 5,657
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- 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.
In the paper
“Here, we focused on the three SHANK genes, which code for large synaptic scaffold proteins of the post-synaptic density [12].”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Introduction
What the sources say
- Not checked yetcites [12] AM Grabrucker, 2011, Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies, Trends Cell Biol source
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“male individuals carrying SHANK1 deletions do not present with language delay or ID and are diagnosed with normal IQ ASD or Asperger syndrome [19].”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Discussion
What the sources say
- Not checked yetcites [19] D Sato, 2012, SHANK1 Deletions in Males with Autism Spectrum Disorder, Am J Hum Genet source
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [42]–[44]
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“The two SHANK3 deletions reported by Glessner et al. (2009) [34] in control subjects have not been validated and should be interpreted with caution.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > Cohorts used for the meta-analysis of SHANK mutations
What the sources say
- Not checked yetcites [34] JT Glessner, 2009, Autism genome-wide copy number variation reveals ubiquitin and neuronal genes, Nature source
Strength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, our genetic and clinical findings provide additional support for considering SHANK mutations in a broad spectrum of patients with ASD.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Discussion
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: The cohorts included in the meta-analysis are representative of the whole ASD population.
In the paper
“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).”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Discussion
What the sources say
- Not checked yetcites [12] AM Grabrucker, 2011, Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies, Trends Cell Biol source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Results > Cohorts used for the meta-analysis of SHANK mutations
What the sources say
- Not checked yetcites [19] D Sato, 2012, SHANK1 Deletions in Males with Autism Spectrum Disorder, Am J Hum Genet source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“other genes involved in the same synaptic pathway, including neurexin and neuroligin genes, appear to be associated with a variety of neuropsychiatric disorders [11].”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Discussion
What the sources say
- Not checked yetcites [11] TC Sudhof, 2008, Neuroligins and neurexins link synaptic function to cognitive disease, Nature source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments > Materials and Methods > SHANK copy-number and coding-sequence variants in ASD
What the sources say
- Not checked yetcites Glessner et al. (2009) source
Strength:plain· not yet calibratedn = 2,519
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.

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

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?

Measuring inconsistency in meta-analyses
Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003) · BMJ · doi:10.1136/bmj.327.7414.557 · Cited by 63,139 · cited 1×
“The Q statistic is a chisquare test for heterogeneity, and the I(2) and Tau(2) are the proportion of observed variance in effect sizes across studies for fixed effect model and random effect model, respectively [55].”
Method
Autism Diagnostic Interview-Revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders
Lord, C., Rutter, M., & Le Couteur, A. (1994) · Journal of Autism and Developmental Disorders · doi:10.1007/bf02172145 · Cited by 9,065 · cited 4×
“In Sweden, in few cases, the Diagnostic Interview for Social and Communication Disorders (DISCO-10) [50] was used instead of the ADI-R.”
MethodInfluential
The Autism Diagnostic Observation Schedule—Generic: A Standard Measure of Social and Communication Deficits Associated with the Spectrum of Autism
Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Leventhal, B. L., DiLavore, P. C., Pickles, A., & Rutter, M. (2000) · Journal of Autism and Developmental Disorders · doi:10.1023/a:1005592401947 · Cited by 7,520 · cited 1×
“The autism-spectrum diagnosis was based on the Autism Diagnostic Interview – Revised (ADI-R) [48] and for some of the patients, the Autism Diagnostic Observation Schedule (ADOS) [49].”
Method
THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL
Clopper, C. J., & Pearson, E. S. (1934) · Biometrika · doi:10.1093/biomet/26.4.404 · Cited by 5,327 · cited 1×
“Prevalence and confidence intervals of single studies were evaluated using Clopper and Pearson method [54].”
Method
Strong association of de novo copy number mutations with autism
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., et al. (2007) · Science · doi:10.1126/science.1138659 · Cited by 2,795 · cited 1×
“For the second patient AUN_007, the deletion covers the exon 22 of SHANK3 and exons 1 to 3 of ACR .”
Background
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · cited 1×
“[32,36,37] and no truncating coding-sequence variation within SHANK1 and SHANK3.”
Background
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084 · cited 2×
“[32,36,37] and no truncating coding-sequence variation within SHANK1 and SHANK3.”
BackgroundResult
Functional impact of global rare copy number variation in autism spectrum disorders
Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., Conroy, J., Magalhaes, T. R., Correia, C., Abrahams, B. S., et al. (2010) · Nature · doi:10.1038/nature09146 · Cited by 2,013 · cited 2×
“SHANK copy-number and coding-sequence variants in ASD SHANK copy-number variants were detected with the Illumina Human 1M-Duo BeadChip, and validated by quantitative PCR as previously described [8,18].”
MethodSelf-citation
Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism
Study, P. A. R. I. S., Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I. C., Soderstrom, H., Giros, B., Leboyer, M., et al. (2003) · Nature Genetics · doi:10.1038/ng1136 · Cited by 1,851 · cited 1×
“In particular, mutations in genes coding for synaptic cell adhesion molecules and scaffold proteins — such as neuroligins, neurexins and SHANK — have been repeatedly reported in individuals with ASD [5–10].”
BackgroundSelf-citation
Neuroligins and neurexins link synaptic function to cognitive disease
Südhof, T. C. (2008) · Nature · doi:10.1038/nature07456 · Cited by 1,849 · cited 2×
“These proteins play a crucial role in the formation and stabilization of synapses [11,12].”
Background
Structural Variation of Chromosomes in Autism Spectrum Disorder
Marshall, C. R., Noor, A., Vincent, J. B., Lionel, A. C., Feuk, L., Skaug, J., Shago, M., Moessner, R., Pinto, D., Ren, Y., et al. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2007.12.009 · Cited by 1,815 · cited 1×
“For the second patient AUN_007, the deletion covers the exon 22 of SHANK3 and exons 1 to 3 of ACR .”
BackgroundSelf-citation
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734 · cited 1×
“[32,36,37] and no truncating coding-sequence variation within SHANK1 and SHANK3.”
BackgroundSelf-citation
Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders
Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsäter, H., et al. (2007) · Nature Genetics · doi:10.1038/ng1933 · Cited by 1,602 · cited 6×
“In three families from France and Canada, the SHANK3 deletions originated from a balanced translocation present in a healthy parent [6,13].”
BackgroundMethodInfluentialSelf-citation
Shank3 mutant mice display autistic-like behaviours and striatal dysfunction
Peça, J., Feliciano, C., Ting, J. T., Wang, W., Wells, M. F., Venkatraman, T. N., Lascola, C. D., Fu, Z., & Feng, G. (2011) · Nature · doi:10.1038/nature09965 · Cited by 1,570 · cited 1×
“Shank3 knock-out mice show self-injurious repetitive grooming, and deficits in social interaction and communication [28–30].”
Background
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes
Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S., Zhang, H., Estes, A., Brune, C. W., Bradfield, J. P., et al. (2009) · Nature · doi:10.1038/nature07953 · Cited by 1,421 · cited 3×
“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.”
BackgroundInfluential
Mapping autism risk loci using genetic linkage and chromosomal rearrangements
The Autism Genome Project Consortium (2007) · Nature Genetics · doi:10.1038/ng1985 · Cited by 1,402 · cited 1×
“In particular, mutations in genes coding for synaptic cell adhesion molecules and scaffold proteins — such as neuroligins, neurexins and SHANK — have been repeatedly reported in individuals with ASD [5–10].”
BackgroundSelf-citation
A copy number variation morbidity map of developmental delay
Cooper, G. M., Coe, B. P., Girirajan, S., Rosenfeld, J. A., Vu, T. H., Baker, C., Williams, C., Stalker, H., Hamid, R., Hannig, V., et al. (2011) · Nature Genetics · doi:10.1038/ng.909 · Cited by 1,351 · cited 4×
“In particular, mutations in genes coding for synaptic cell adhesion molecules and scaffold proteins — such as neuroligins, neurexins and SHANK — have been repeatedly reported in individuals with ASD [5–10].”
BackgroundResultInfluential
Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism
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., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.002 · Cited by 1,263
Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting
Betancur, C. (2011) · Brain Research · doi:10.1016/j.brainres.2010.11.078 · Cited by 954
Self-citation
Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function
Won, H., Lee, H.-R., Gee, H. Y., Mah, W., Kim, J.-I., Lee, J., Ha, S., Chung, C., Jung, E. S., Cho, Y. S., et al. (2012) · Nature · doi:10.1038/nature11208 · Cited by 695
The Diagnostic Interview for Social and Communication Disorders: background, inter‐rater reliability and clinical use
Wing, L., Leekam, S. R., Libby, S. J., Gould, J., & Larcombe, M. (2002) · Journal of Child Psychology and Psychiatry · doi:10.1111/1469-7610.00023 · Cited by 694 · cited 1×
“In Sweden, in few cases, the Diagnostic Interview for Social and Communication Disorders (DISCO-10) [50] was used instead of the ADI-R.”
Method
Contribution of SHANK3 Mutations to Autism Spectrum Disorder
Moessner, R., Marshall, C. R., Sutcliffe, J. S., Skaug, J., Pinto, D., Vincent, J., Zwaigenbaum, L., Fernandez, B., Roberts, W., Szatmari, P., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/522590 · Cited by 681 · cited 5×
“In the Canadian family, the elder sister carrying the SHANK3 duplication was diagnosed with attentiondeficit/hyperactivity disorder (ADHD) and developmental delay [13].”
BackgroundInfluentialSelf-citation
Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
Schmeisser, M. J., Ey, E., Wegener, S., Bockmann, J., Stempel, A. V., Kuebler, A., Janssen, A.-L., Udvardi, P. T., Shiban, E., Spilker, C., et al. (2012) · Nature · doi:10.1038/nature11015 · Cited by 638 · cited 1×
“Shank2 knock-out mice show hyperactivity, increased anxiety, repetitive grooming, and abnormalities in vocal and social behaviors [26,27].”
BackgroundSelf-citation
Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation
Berkel, S., Marshall, C. R., Weiss, B., Howe, J., Roeth, R., Moog, U., Endris, V., Roberts, W., Szatmari, P., Pinto, D., et al. (2010) · Nature Genetics · doi:10.1038/ng.589 · Cited by 563 · cited 3×
“Few studies have explored SHANK1 and SHANK2 in ASD, but all have led to the conclusion that deleterious mutations in these genes contribute to the disorder [14,18,19].”
BackgroundMethodInfluentialSelf-citation
Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr212 · Cited by 537 · cited 1×
“Shank3 knock-out mice show self-injurious repetitive grooming, and deficits in social interaction and communication [28–30].”
Background
Advances in Autism
Geschwind, D. H. (2009) · Annual Review of Medicine · doi:10.1146/annurev.med.60.053107.121225 · Cited by 512
Modeling Autism by SHANK Gene Mutations in Mice
Jiang, Y.-H., & Ehlers, M. D. (2013) · Neuron · doi:10.1016/j.neuron.2013.03.016 · Cited by 488 · cited 1×
“Mice lacking any of the SHANK proteins display phenotypes relevant to ASD [23].”
Background
The Genetic Landscapes of Autism Spectrum Disorders
Huguet, G., Ey, E., & Bourgeron, T. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153431 · Cited by 486 · cited 2×
“In particular, chromosomal rearrangements, rare de novo copy-number variants and de novo coding-sequence variants may account for more than 20% of the cases [1,2].”
BackgroundSelf-citation
SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients
Shcheglovitov, A., Shcheglovitova, O., Yazawa, M., Portmann, T., Shu, R., Sebastiano, V., Krawisz, A., Froehlich, W., Bernstein, J. A., Hallmayer, J. F., et al. (2013) · Nature · doi:10.1038/nature12618 · Cited by 470 · cited 1×
“This clinical screening should: (i) improve the quality of genetic counseling of ASD and ID for patients and their family relatives; (ii) increase our understanding of the clinical features associated with SHANK mutations together with the developmental trajectories of the patients [39], (ii) enable the development of…”
Background
The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)
Phelan, K., & McDermid, H. E. (2011) · Molecular Syndromology · doi:10.1159/000334260 · Cited by 460 · cited 3×
“In addition, sequence gaps and annotation errors of SHANK2 and SHANK3 in the human genome assembly (hg19) have led to incorrect interpretations of sequencing results obtained in patients [15].”
BackgroundInfluential
Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data
Friedrich, J. O., Adhikari, N. K. J., & Beyene, J. (2007) · BMC Medical Research Methodology · doi:10.1186/1471-2288-7-5 · Cited by 460 · cited 1×
“Zero total event studies (no events in both ASD and controls) were included [56].”
Background
Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders
Leblond, C. S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., Konyukh, M., Chaste, P., Ey, E., Rastam, M., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002521 · Cited by 429 · cited 6×
“For SHANK1 and SHANK2 , the sequencing protocol was adapted from Leblond et al. (2012) [18] and Sato et al. (2012) [19] (Table S8).”
BackgroundMethodResultInfluentialSelf-citation
A de novo convergence of autism genetics and molecular neuroscience
Krumm, N., O’Roak, B. J., Shendure, J., & Eichler, E. E. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.11.005 · Cited by 423 · cited 1×
“This coverage issue of SHANK3 was indeed observed by other groups [38].”
Background
Reduced Excitatory Neurotransmission and Mild Autism-Relevant Phenotypes in Adolescent Shank3 Null Mutant Mice
Yang, M., Bozdagi, O., Scattoni, M. L., Wöhr, M., Roullet, F. I., Katz, A. M., Abrams, D. N., Kalikhman, D., Simon, H., Woldeyohannes, L., et al. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.6107-11.2012 · Cited by 369 · cited 1×
“Shank3 knock-out mice show selfinjurious repetitive grooming, and deficits in social interaction and communication [28–30].”
Background
De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia
Gauthier, J., Champagne, N., Lafrenière, R. G., Xiong, L., Spiegelman, D., Brustein, E., Lapointe, M., Peng, H., Côté, M., Noreau, A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906232107 · Cited by 369 · cited 2×
“(2009–2010) [16,47]]’’, 8 = ‘‘Moessner et al.”
BackgroundSelf-citation
Smaller Dendritic Spines, Weaker Synaptic Transmission, but Enhanced Spatial Learning in Mice Lacking Shank1
Hung, A. Y., Futai, K., Sala, C., Valtschanoff, J. G., Ryu, J., Woodworth, M. A., Kidd, F. L., Sung, C. C., Miyakawa, T., Bear, M. F., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3032-07.2008 · Cited by 350 · cited 1×
“Shank1 knock-out mice show increased anxiety, decreased vocal communication, decreased locomotion and remarkably, enhanced working memory, but decreased longterm memory [24,25].”
Background
Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency
Soorya, L. V., Kolevzon, A. L., Zweifach, J., Lim, T., Dobry, Y., Schwartz, L., Frank, Y., Wang, A. T., Cai, G., Parkhomenko, E., et al. (2013) · Molecular Autism · doi:10.1186/2040-2392-4-18 · Cited by 345 · cited 1×
“Deletions, duplications and coding mutations in the SHANK genes have been recurrently reported in patients with ASD [6,8– 10 ,13– 20].”
BackgroundSelf-citation
Key role for gene dosage and synaptic homeostasis in autism spectrum disorders
Toro, R., Konyukh, M., Delorme, R., Leblond, C., Chaste, P., Fauchereau, F., Coleman, M., Leboyer, M., Gillberg, C., & Bourgeron, T. (2010) · Trends in Genetics · doi:10.1016/j.tig.2010.05.007 · Cited by 331 · cited 2×
“The synapse has therefore emerged as a common target for the different genetic mutations that affect chromatin remodeling, synaptic translation, formation and functioning [4].”
BackgroundSelf-citation
Novel de novo SHANK3 mutation in autistic patients
Gauthier, J., Spiegelman, D., Piton, A., Lafrenière, R. G., Laurent, S., St‐Onge, J., Lapointe, L., Hamdan, F. F., Cossette, P., Mottron, L., et al. (2009) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30822 · Cited by 321 · cited 4×
“(2009–2010) [16,47]]’’, 8 = ‘‘Moessner et al.”
BackgroundInfluentialSelf-citation
SHANK1 Deletions in Males with Autism Spectrum Disorder
Sato, D., Lionel, A. C., Leblond, C. S., Prasad, A., Pinto, D., Walker, S., O'Connor, I., Russell, C., Drmic, I. E., Hamdan, F. F., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.03.017 · Cited by 318 · cited 11×
“4 kb altering both the synaptotagmin-3 gene (SYT3) and SHANK1 was detected in a Swedish male with normal IQ and ASD [19].”
BackgroundMethodResultInfluentialSelf-citation
SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism
Durand, C. M., Perroy, J., Loll, F., Perrais, D., Fagni, L., Bourgeron, T., Montcouquiol, M., & Sans, N. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.57 · Cited by 316 · cited 1×
“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].”
BackgroundSelf-citation
Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders
Boccuto, L., Lauri, M., Sarasua, S. M., Skinner, C. D., Buccella, D., Dwivedi, A., Orteschi, D., Collins, J. S., Zollino, M., Visconti, P., et al. (2013) · European Journal of Human Genetics · doi:10.1038/ejhg.2012.175 · Cited by 240 · cited 4×
“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).”
BackgroundMethodInfluential
The emerging role of SHANK genes in neuropsychiatric disorders
Guilmatre, A., Huguet, G., Delorme, R., & Bourgeron, T. (2014) · Developmental Neurobiology · doi:10.1002/dneu.22128 · Cited by 237 · cited 1×
“This clinical screening should: (i) improve the quality of genetic counseling of ASD and ID for patients and their family relatives; (ii) increase our understanding of the clinical features associated with SHANK mutations together with the developmental trajectories of the patients [39], (ii) enable the development of…”
BackgroundSelf-citation
Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies
Grabrucker, A. M., Schmeisser, M. J., Schoen, M., & Boeckers, T. M. (2011) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.07.003 · Cited by 233 · cited 3×
“Here, we focused on the three SHANK genes, which code for large synaptic scaffold proteins of the post-synaptic density [12].”
BackgroundSelf-citation
Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome
Bonaglia, M. C., Giorda, R., Beri, S., De Agostini, C., Novara, F., Fichera, M., Grillo, L., Galesi, O., Vetro, A., Ciccone, R., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002173 · Cited by 224 · cited 2×
“(2012) [21] found an increase in NMDA currents, while Won et al.”
Background
Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior
Wöhr, M., Roullet, F. I., Hung, A. Y., Sheng, M., & Crawley, J. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020631 · Cited by 220 · cited 1×
“Shank1 knock-out mice show increased anxiety, decreased vocal communication, decreased locomotion and remarkably, enhanced working memory, but decreased longterm memory [24,25].”
Background
Progress toward treatments for synaptic defects in autism
Delorme, R., Ey, E., Toro, R., Leboyer, M., Gillberg, C., & Bourgeron, T. (2013) · Nature Medicine · doi:10.1038/nm.3193 · Cited by 218 · cited 2×
“in order to identify the factors that influence the clinical trajectory, clinical manifestations, and outcome of affected individuals [41].”
BackgroundSelf-citation
SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders
Betancur, C., & Buxbaum, J. D. (2013) · Molecular Autism · doi:10.1186/2040-2392-4-17 · Cited by 189 · cited 2×
“In more than 80% of the cases, autism or autistic-like behavior is present [22].”
BackgroundSelf-citation
Autism-Associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin–Neuroligin-Mediated Transsynaptic Signaling
Arons, M. H., Thynne, C. J., Grabrucker, A. M., Li, D., Schoen, M., Cheyne, J. E., Boeckers, T. M., Montgomery, J. M., & Garner, C. C. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.2215-12.2012 · Cited by 180
Self-citation
Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders
Schaaf, C. P., Sabo, A., Sakai, Y., Crosby, J., Muzny, D., Hawes, A., Lewis, L., Akbar, H., Varghese, R., Boerwinkle, E., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr243 · Cited by 175 · cited 1×
“96) (Table 1, S5 & S11, and Figure 1 & 3) [6,13,16,17,35].”
Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology
Berkel, S., Tang, W., Treviño, M., Vogt, M., Obenhaus, H. A., Gass, P., Scherer, S. W., Sprengel, R., Schratt, G., & Rappold, G. A. (2012) · Human Molecular Genetics · doi:10.1093/hmg/ddr470 · Cited by 162 · cited 1×
“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].”
BackgroundSelf-citation
Breakpoint mapping by next generation sequencing reveals causative gene disruption in patients carrying apparently balanced chromosome rearrangements with intellectual deficiency and/or congenital malformations
Schluth‐Bolard, C., Labalme, A., Cordier, M., Till, M., Nadeau, G., Tevissen, H., Lesca, G., Boutry‐Kryza, N., Rossignol, S., Rocas, D., et al. (2013) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2012-101351 · Cited by 122 · cited 1×
“For patient AUL_001, the breakpoints were previously sequenced using whole genome sequencing [31] (Table 2, Figure S4 and Text S1).”
MethodSelf-citation
Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: Presence of bipolar disorder and progressive loss of skills
Denayer, A., Van Esch, H., de Ravel, T., Frijns, J.-P., Van Buggenhout, G., Vogels, A., Devriendt, K., Geutjens, J., Thiry, P., & Swillen, A. (2012) · Molecular Syndromology · doi:10.1159/000339119 · Cited by 99 · cited 2×
“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…”
BackgroundResult
Meta-analysis of incidence of rare events
Lane, P. W. (2012) · Statistical Methods in Medical Research · doi:10.1177/0962280211432218 · Cited by 98 · cited 1×
“If any contingency tables contained zero values, a continuity correction was applied to the relevant tables [57].”
Method
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci
Chilian, B., Abdollahpour, H., Bierhals, T., Haltrich, I., Fekete, G., Nagel, I., Rosenberger, G., & Kutsche, K. (2013) · Clinical Genetics · doi:10.1111/cge.12105 · Cited by 85 · cited 1×
“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…”
Result
Olfactory Receptor-Related Duplicons Mediate a Microdeletion at 11q13.2q13.4 Associated with a Syndromic Phenotype
Wischmeijer, A., Magini, P., Giorda, R., Gnoli, M., Ciccone, R., Cecconi, I., Franzonı, E., Mazzanti, L., Romeo, G., Zuffardi, O., et al. (2010) · Molecular Syndromology · doi:10.1159/000322054 · Cited by 42 · cited 1×
“These clinical signs are unspecific, but were also reported in patients with ASD with more complex chromosomal rearrangements encompassing SHANK2 [33].”
Etiological Heterogeneity in Autism Spectrum Disorders
Betancur, C., & Coleman, M. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-391924-3.00008-9 · Cited by 28
Self-citation
Screening for copy number alterations in loci associated with autism spectrum disorders by two‐color multiplex ligation‐dependent probe amplification
Bremer, A., Giacobini, M., Nordenskjöld, M., Brøndum‐Nielsen, K., Mansouri, M., Dahl, N., Anderlid, B., & Schoumans, J. (2010) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30954 · Cited by 17 · cited 1×
“For SHANK copy-number variants, a total of 5 657 cases and 19 163 controls were included, representing 11 studies including this one (Table S3) [8,9,13,14,18,19,34,35,51–53].”
Background

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Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci
Sanders, S. J., He, X., Willsey, A. J., Ercan-Sencicek, A. G., Samocha, K. E., Cicek, A. E., Murtha, M. T., Bal, V. H., Bishop, S. L., Dong, S., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.016 · Cited by 1,430
“All eight loci (Table 2) have previously been implicated in ASD (Bucan et al., 2009; Kumar et al., 2008; Leblond et al., 2014; Marshall et al., 2008; Mefford et al., 2008; Moreno-De-Luca et al., 2013b; Sanders et al., 2011; Weiss et al., 2008).”
BackgroundResult
From the genetic architecture to synaptic plasticity in autism spectrum disorder
Bourgeron, T. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3992 · Cited by 975
Self-citation
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
C Yuen, R. K., Merico, D., Bookman, M., L Howe, J., Thiruvahindrapuram, B., Patel, R. V., Whitney, J., Deflaux, N., Bingham, J., Wang, Z., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4524 · Cited by 844
“Dozens of susceptibility genes (for example, SHANK - and NRXN -family genes) 11,12 and copy number variation (CNV) loci (for example, 16p11.”
Self-citation
SHANK proteins: roles at the synapse and in autism spectrum disorder
Monteiro, P., & Feng, G. (2017) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.183 · Cited by 681
Adult restoration of Shank3 expression rescues selective autistic-like phenotypes
Mei, Y., Monteiro, P., Zhou, Y., Kim, J.-A., Gao, X., Fu, Z., & Feng, G. (2016) · Nature · doi:10.1038/nature16971 · Cited by 392

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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: Leblond, Claire S.
Nava, Caroline
Huguet, Guillaume
Lumbroso, Serge
Giuliano, Fabienne
Depienne, Christel
Pinto, Dalila
Durand, Christelle M.
Ey, Elodie
Toro, Roberto
Peyre, Hugo
Mathieu, Alexandre
Rappold, Gudrun A.
Monaco, Anthony P.
Maestrini, Elena
Galan, Pilar
Jacquette, Aurélia
Afenjar, Alexandra
Brice, Alexis
Laffargue, Fanny
Rivier, François
Bonneau, Dominique
Lathrop, Mark
Sanlaville, Damien
Edery, Patrick
Schmeisser, Michael J.
Boeckers, Tobias M.
Sato, Daisuke
Scherer, Stephen W.
Rouleau, Guy A.
Betancur, Catalina
Leboyer, Marion
Gillberg, Christopher
Delorme, Richard
Bourgeron, Thomas
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: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
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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Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

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